RARE DISEASE
Microvillus inclusion disease
Microvillus inclusion disease
Microvillus inclusion disease
Synonyms: Congenital microvillous atrophy, Congenital microvillus atrophy, MVID, Microvillous inclusion disease
Synonyms: Congenital microvillous atrophy, Congenital microvillus atrophy, MVID, Microvillous inclusion disease
Synonyms: Congenital microvillous atrophy, Congenital microvillus atrophy, MVID, Microvillous inclusion disease
Drug discovery
5
drugs
With orphan designations
Overview
Microvillus inclusion disease (MVID) is an autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea starting in early infancy, caused by MYO5B, STX3, or STXBP2 mutations. These mutations disrupt enterocyte apical trafficking, resulting in malabsorption, microvillus atrophy, and cytoplasmic inclusions. Diagnosis relies on duodenal biopsy with electron microscopy. Management requires life-long parenteral nutrition (PN), though complications like PN-associated liver disease and sepsis are common. Intestinal transplantation remains the only curative option but carries significant risks [1][5][16][19].
Burden
Therapies
Parenteral nutrition: Lifelong requirement for 90% of patients, with intestinal transplantation considered for PN failure (5-year survival ~60%) [3][11][19]
Pharmacological: Limited efficacy; antisecretory agents (e.g., Crofelemer) may reduce stool output in select cases [3][7]
Experimental: Gamma-secretase inhibitors (e.g., DAPT) show reversal of microvillus defects in enteroid models [7][14]
Categories: rare gastroenterological diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
82 drug discovery papers about Microvillus inclusion disease, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
82 drug discovery papers about Microvillus inclusion disease, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-09-01 | 245.9: Adult intestinal transplant program at King Faisal specialist hospital and research center, Riyadh, KSA.
Introduction: Worldwide there still is limited access to transplantation for patients suffering of intestinal failure with TPN associated complications. Despite favorable and improving outcomes there are still reluctancies to answer the obvious need for intestinal transplantation. Methods: An intestinal transplant program was started at King Faisal Hospital and Research Center in Riyadh, Kingdom of Saudi Arabia in October 2017. A total of 11 adult intestinal transplants (ITX) have been performed in 11 recipients with a follow up of 2.8 years. The outcomes herein were analyzed retrospectively by a prospectively designed database. Results: Mean recipient age at time of transplant was 25 years for 6 male and 5 female recipients. Mean duration of total parenteral nutrition (TPN) prior ITX amounted to 34 months. Underlying disease was surgical short bowel syndrome in 5 patients. An additional 5 recipients were transplanted for intestinal motility disorder and 1 for microvillous inclusion disease. In case of intestinal failure associated liver disease (IFALD) pre-transplant liver biopsy was performed in order to rule out irreversible liver pathologies. All patients received a full intestinal allograft including the right hemicolon. Mean cold ischemic times were 218 minutes (range 75-335) and 24 minutes for warm ischaemia (range 17-40). Median length of hospital stay was 61 days (range 21-320). For endoscopic monitoring all recipients received a chimney stoma at the ileal region. All but one patient were discharged without any further TPN nor i.v.- fluid therapy. All of the recipients receiving thymoglobulin induction (n=3) developed biopsy proven rejection within the first year post ITX, whereas only 50% (4 out of 8) did following alemtuzumab induction. Rejections were monitored by protocol biopsies and HLA surveillance. Treatment consisted of steroid pulse, additional antibody administartion (ATG, Alemtuzumab, Infliximab, Vedolizumab, Rituximab), plasma exchange, immunoglobulins or their combination as per nature of the individual rejection. Immunosuppressive maintenance consisted of FK 506/steroids for the first 6 weeks followed by FK 506/mTor inhibition after stoma closure +-steroid withdrawal. 1-, 3- and 5-year survival are 91, 64 and 64 percent. Patient death were sepsis in 2 recipients following non-compliance induced rejections at 8 and 18, self-induced i.v. overdosing for 1 at 18 and a septic shock at 12. Death censored allograft survival was 100%. Average BMI increased from 18 before to 20 one year post transplant. GvHD and PTLD incidence was 0%. 2 recipients developed severe CMV disease with CMV enteritis, being resolved following intensified management. Conclusion: ITX provides a challenging but valuable and life-changing therapeutical option for patients suffering of intestinal failure. It should be considered timely to avoid progression of IFALD with the necessity for combined liver and intestinal or multivisceral transplantation.
2023-01-13 | TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration
SUMMARY The adult gut epithelium has a remarkable ability to recover from damage. To achieve cellular therapies aimed at restoring and/or replacing defective gastrointestinal tissue, it is important to understand the natural mechanisms of tissue regeneration. We employed a combination of high throughput sequencing approaches, mouse genetic models, and murine and human organoid models, and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. Depletion of macrophages or genetic disruption of TGFB-signaling significantly impaired the regenerative response following irradiation. Murine intestinal regeneration is also characterized by a process where a fetal transcriptional signature is induced during repair. In organoid culture, TGFB1-treatment was necessary and sufficient to induce a transcriptomic shift to the fetal-like/regenerative state. The regenerative response was enhanced by the function of mesenchymal cells, which are also primed for regeneration by TGFB1. Mechanistically, integration of ATAC-seq, scRNA-seq, and ChIP-seq suggest that a regenerative YAP-SOX9 transcriptional circuit is activated in epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for the application of the TGFB-induced regenerative circuit in cellular therapy. GRAPHIC ABSTRACT
2021-07-26 | Microvillus Inclusion Disease: Can Mesenchymal Stem Cells Be a Potential Treatment Option?
Microvillus inclusion disease (MVID; MIM #251850), is a rare life-threatening secretory and malabsorptive diarrhea of infancy due to mutations in the MYO5B gene.A 6-day-old male patient was referred to our neonatal intensive care unit for profuse diarrhea beginning on the 2nd day of life causing 17% weight loss, metabolic acidosis and hyponatremia.Our patient had a homozygous mutation in the MYO5B gene.On 110th day of life, mesenchymal stem cell treatment (1x106 cells trans duodenal and 2x106 cells intravenous) was administered.Although fluid and electrolyte requirements did not decrease after stem cell therapy, the rate of blood stream infections was reduced.Small bowel transplantation using cadaveric intestine was performed at the age of 20 months.Unfortunately, the infant died of sepsis one month after transplantation.In this case report, results of stem cell therapy in a newborn infant with MVID were presented and discussed with the relevant literature.
2019-06-01 | GP248 Mesenchymal stem cell therapy in microvillus inclusion disease
Microvillus inclusion disease (MVID; MIM #251850), is a rare life-threatening secretory and malabsorptive diarrhea of infancy due to mutations in the Myosin 5B (MYO5B) gene. Most of the patients die before achieving the opportunity of bowel transplantation due to electrolytes and renal tubular function disturbances and complications of parenteral nutrition. In this case report, results of stem cell therapy in a newborn infant with MVID were presented and discussed with the relevant literature. A 6-day-old male patient was referred to our NICU for profuse diarrhea beginning on the postnatal 2nd day after birth, metabolic acidosis and hyponatremia. He was born at 36+4 gestational weeks as the fourth child of nonconsanguineous parents. Second and third siblings died at 2 and 3,5 months due to complications of intractable diarrhea. Third child's exom sequencing identified a homozygous, disease-causing nonsense variant C.4399C>T (p.Gin1467*) in the MYO5B gene. Both parents were heterozygous for the mutation and they did not accept prenatal diagnosis. Our patient was also affected by homozygous mutation in MYO5B gene. With the knowledge of past history, total parenteral nutrition was started and maximum effort was directed to maintain fluid and electrolyte equilibrium. Patient had high fluid (350 ml/kg/day), sodium (20–25 meq/kg/day) and bicarbonate requirements (12–18 meq/kg/day). On 110th day of life mesenchymal stem cells (1x106 Ü transduodenal and 2x106 Ü IV) were administered. Although fluid and electrolyte requirements did not decrease after 2 months of follow up after stem cell therapy, the rate of blood stream infections was reduced. In MVID, mutations in the MYO5B gene which encodes a protein called myosin Vb contribute to the dysfunction of enterocytes. Survival rate is less than 25% at the age of 9 months. Mortality rate is also high after bowel transplantation. Recently, stem cell therapy was presented as a promising alternative strategy for overcoming the current limitations of intestinal failure treatment. We concluded that, the reason why our patient did not benefit from the treatment was rapid turnover of the intestine epithelial cells and the lack of receptive surface caused by the genetic defect. Furthermore, using modified intestinal stem cells instead of mesenchymal stem cells may be more beneficial. In our patient, decreased incidence of infection with probable immunomodulatory effects of stem cells was the secondary gain.
2016-10-18 | The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.
Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.
small molecules
2026-07-17 | Long-term clinical trajectory of microvillus inclusion disease associated with STXBP2-related familial hemophagocytic lymphohistiocytosis type 5: A case report.
Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin-binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long-term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22-year-old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long-term follow-up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long-term extrahematopoietic phenotype of STXBP2-related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.
2026-05-20 | The UNC45A–MYO5B Axis in Enterohepatic Disorders
Defects in epithelial polarity and apical trafficking underlie a spectrum of rare enterohepatic disorders, including microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC/PFIC). This thesis investigates the molecular relationship between the myosin co-chaperone UNC45A and the motor protein MYO5B, two proteins associated with overlapping intestinal and hepatic phenotypes.
Using intestinal epithelial and hepatocellular models, this work demonstrates that UNC45A is required for MYO5B protein stability and proper Rab11A-dependent apical recycling trafficking. Loss of UNC45A disrupts epithelial polarity, impairs microvillus formation, and induces MVID-like cellular defects. Mechanistic studies further show that specific UNC45A variants impair protein stability and chaperone-associated trafficking pathways. In addition, this thesis explores the pathogenesis of MYO5B-associated cholestasis and evaluates the therapeutic potential of ileal bile acid transporter inhibition in UNC45A-associated cholestatic disease.
Together, these findings establish a functional UNC45A–MYO5B axis linking rare enteropathic and cholestatic disorders at the molecular level and provide new insights into the regulation of epithelial polarity and apical membrane trafficking in the enterohepatic system.
2026-03-30 | Microvillus inclusion disease-associated MYO5B deficiency impairs endosome-to-mitochondrion iron transfer.
MYO5B deficiency causes microvillus inclusion disease (MVID), characterized by the inability to absorb dietary nutrients and secretory diarrhea. MVID intestinal tissue shows metabolic abnormalities, but the causality with MYO5B and the underlying mechanism are unknown. The aim of this study was to determine the effects of MYO5B deficiency on mitochondria as key regulators of cellular metabolism and the underlying mechanism. Intestinal tissue from MVID patients and inducible intestine-specific myo5b-knockout (KO) mouse were examined by using light and large-scale scanning transmission electron microscopy. CRISPR-Cas9 was used to generate MYO5B KO intestinal Caco2 cells. Site-directed mutagenesis was performed to generate MYO5B mutants. Fluorescence-based indicators of mitochondrial membrane potential and iron levels, analyses of carbonylated protein residues from isolated mitochondria, and high-resolution respirometry were used to assess mitochondrial homeostasis and function. MYO5B-deficient Caco2 cells showed fragmented and swollen mitochondria, reduced intra-mitochondrial cristae, defective aerobic respiration, reduced mitochondrial membrane potential, and increased mitochondrial oxidative stress. Introduction of a myc-tagged full-length MYO5B in MYO5B KO cells restored membrane potential, whereas the MVID-causing MYO5B-p.(Pro660Leu) variant and the MYO5B-p.(Lys1534Ala) and -p.(Leu1597Pro) mutants did not, demonstrating causality. Quantitative 3D fluorescence microscopy revealed close associations between mitochondria and MYO5B-positive endosomes carrying the iron-transporting transferrin. Associations between transferrin-loaded endosomes and mitochondria were diminished in MYO5B-depleted Caco2 cells. MYO5B-deficient Caco2 cells showed reduced mitochondrial iron content and an accumulation of iron in the endosomal system. MYO5B deficiency impairs endosome-to-mitochondrial iron transfer, leading to mitochondrial dysfunction. These results offer a novel therapeutic avenue aimed at restoring mitochondrial function in MVID.
2025-12-08 | Microvillus Inclusion Disease: Successful Treatment of Severe Hyponatremia With High-Dose Fludrocortisone via a Possible Gut-Mediated Mechanism.
Microvillus inclusion disease (MVID) is a rare congenital enteropathy marked by severe secretory diarrhea and malabsorption due to microvillous atrophy secondary to accumulation of secretory granules in the apical cytoplasm of enterocytes. Management is supportive with parenteral nutrition and emergent management of acute electrolyte disturbances. We report an 8-month-old male infant with genetically confirmed MVID (MYO5B mutation) who developed life-threatening hyponatremia (serum sodium 118 mmol/L) despite maximal sodium supplementation (>300 mmol/d = 49 mmol/kg/d) and negligible urinary sodium level. High-dose fludrocortisone (100 mcg bid; 28.4 mcg/kg/d) successfully restored serum sodium levels and reduced stool output, with normalization of renin and aldosterone, without adverse effects. This case demonstrates a potential therapeutic benefit of gastrointestinal mineralocorticoid receptor agonism in managing severe hyponatremia in patients with MVID during periods of acute decompensation.
2025-04-30 | LPAR5 as a prospective therapeutic target for treating microvillus inclusion disease
1. Microvillus inclusion disease (MVID) is a rare congenital diarrheal disorder that typically presents within the first week of life manifesting in severe dehydration and malnutrition. The small i...
gene therapies
2026-08-12 | Enterocyte trafficking proteins and the pathophysiological consequences of their sortopathies
Abstract Objective We synthesised current evidence on enterocyte trafficking proteins and elucidated the molecular mechanisms by which their dysfunction contributes to intestinal disease. Methods Search was conducted in PubMed/MEDLINE, Web of Science, and Wiley Online Library for studies published between January 2000 and March 2026, following PRISMA 2020 guidelines. Studies involving enterocyte trafficking proteins were included based on predefined PICO criteria. Results Thirty-six studies were included, identifying key trafficking regulators, including Rab8a, Rab11a, MYO5B, MYO1A, MYO6, syntaxin 3, MUNC18-2, and SNX27, as essential for enterocyte protein sorting and polarity. Six major mechanisms of dysfunction were observed, involving defects in protein maturation, vesicle formation, Rab-mediated trafficking, SNARE-dependent fusion, motor-driven transport, and endosomal recycling. These disruptions converge into three main pathological processes: impaired apical delivery, defective endocytic retrieval, and failed exocytic fusion, ultimately leading to severe congenital enteropathies such as microvillus inclusion disease, chylomicron retention disease, and STXBP2-associated enteropathy. Conclusion Enterocyte trafficking proteins are fundamental determinants of epithelial polarity and intestinal function. Their dysfunction drives a spectrum of severe intestinal disorders through converging mechanisms of protein mislocalisation and barrier disruption. Advancing diagnostic approaches and developing targeted therapies aimed at restoring intracellular trafficking pathways represent critical priorities for improving patient outcomes.
2022-04-11 | A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy
UNC45A is a myosin (co-)chaperone, and mutations in the UNC45A gene were recently identified in osteo-oto-hepato-enteric (O2HE) syndrome patients presenting with congenital diarrhea and intrahepatic cholestasis. Congenital diarrhea and intrahepatic cholestasis are also the prime symptoms in patients with microvillus inclusion disease (MVID) and mutations in MYO5B, encoding the recycling endosome-associated myosin Vb. The aim of this study was to determine whether UNC45A and myosin Vb are functionally linked.CRISPR-Cas9 gene editing and site-directed mutagenesis were performed with intestinal epithelial and hepatocellular cell lines, followed by Western blotting, quantitative polymerase chain reaction, and scanning electron and/or confocal fluorescence microscopy to determine the relationship between (mutants of) UNC45A and myosin Vb.UNC45A depletion in intestinal and hepatic cells reduced myosin Vb protein expression, and in intestinal epithelial cells, it affected 2 myosin Vb-dependent processes that underlie MVID pathogenesis: rat sarcoma-associated binding protein (RAB)11A-positve recycling endosome positioning and microvilli development. Reintroduction of UNC45A in UNC45A-depleted cells restored myosin Vb expression, and reintroduction of UNC45A or myosin Vb, but not the O2HE patient UNC45A-c.1268T>A variant, restored recycling endosome positioning and microvilli development. The O2HE patient-associated p.V423D substitution, encoded by the UNC45A-c.1268T>A variant, impaired UNC45A protein stability but as such not the ability of UNC45A to promote myosin Vb expression and microvilli development.A functional relationship exists between UNC45A and myosin Vb, thereby connecting 2 rare congenital diseases with overlapping enteropathy at the molecular level. Protein instability rather than functional impairment underlies the pathogenicity of the O2HE syndrome-associated UNC45A-p.V423D mutation.
2021-02-17 | Editing Myosin VB Gene to Create Porcine Model of Microvillus Inclusion Disease, With Microvillus-Lined Inclusions and Alterations in Sodium Transporters.
Microvillus inclusion disease (MVID) is caused by inactivating mutations in the myosin VB gene (MYO5B). MVID is a complex disorder characterized by chronic, watery, life-threatening diarrhea that usually begins in the first hours to days of life. We developed a large animal model of MVID to better understand its pathophysiology. Pigs were cloned by transfer of chromatin from swine primary fetal fibroblasts, which were edited with TALENs and single-strand oligonucleotide to introduce a P663-L663 substitution in the endogenous swine MYO5B (corresponding to the P660L mutation in human MYO5B, associated with MVID) to fertilized oocytes. We analyzed duodenal tissues from patients with MVID (with the MYO5B P660L mutation) and without (controls), and from pigs using immunohistochemistry. Enteroids were generated from pigs with MYO5B(P663L) and without the substitution (control pigs). Duodenal tissues from patients with MVID lacked MYO5B at the base of the apical membrane of intestinal cells; instead MYO5B was intracellular. Intestinal tissues and derived enteroids from MYO5B(P663L) piglets had reduced apical levels and diffuse subapical levels of sodium hydrogen exchanger 3 and SGLT1, which regulate transport of sodium, glucose, and water, compared with tissues from control piglets. However, intestinal tissues and derived enteroids from MYO5B(P663L) piglets maintained CFTR on apical membranes, like tissues from control pigs. Liver tissues from MYO5B(P663L) piglets had alterations in bile salt export pump, a transporter that facilitates bile flow, which is normally expressed in the bile canaliculi in the liver. We developed a large animal model of MVID that has many features of the human disease. Studies of this model could provide information about the functions of MYO5B and MVID pathogenesis, and might lead to new treatments.
2019-12-05 | Recent advances in understanding and managing malabsorption: focus on microvillus inclusion disease
Microvillus inclusion disease (MVID) is a rare congenital severe malabsorptive and secretory diarrheal disease characterized by blunted or absent microvilli with accumulation of secretory granules and inclusion bodies in enterocytes. The typical clinical presentation of the disease is severe chronic diarrhea that rapidly leads to dehydration and metabolic acidosis. Despite significant advances in our understanding of the causative factors, to date, no curative therapy for MVID and associated diarrhea exists. Prognosis mainly relies on life-long total parenteral nutrition (TPN) and eventual small bowel and/or liver transplantation. Both TPN and intestinal transplantation are challenging and present with many side effects. A breakthrough in the understanding of MVID emanated from seminal findings revealing mutations inMYO5Bas a cause for MVID. During the last decade, many studies have thus utilized cell lines and animal models with knockdown ofMYO5Bto closely recapitulate the human disease and investigate potential therapeutic options in disease management. We will review the most recent advances made in the research pertaining to MVID. We will also highlight the tools and models developed that can be utilized for basic and applied research to increase our understanding of MVID and develop novel and effective targeted therapies.
2015-07-23 | Myo5b knockout mice as a model of microvillus inclusion disease
Abstract Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b . Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.
proteins
2026-02-12 | Myosin 5b deficiency alters liver proliferation, zonation, and bile acid composition.
Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b's role in the intestine is well characterized, its function in the liver remains unclear. To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
2025-07-30 | Microvillus inclusion disease: a short review of literature.
Microvillus inclusion disease (MVD) is a rare autosomal recessive disease that was first discovered in 1978 by Davidson et al., with significant mortality and morbidity within the first year of life. It presents mainly with abdominal symptoms like diarrhoea, abdominal distension, vomiting electrolyte imbalance. Sometimes, depending on the genetic mutation involved, the phenotypic manifestation can vary. Certain genetic mutations are associated with cholestasis, dilated bowel loops, and metabolic acidosis, whereas some present with nystagmus and reduced visual acuity. Electron microscopy of the duodenal biopsy sample is used as a diagnostic tool. Absence or shortening of apical microvilli with microvillus inclusion bodies in mature enterocytes, which are pathognomonic to MVD alongside periodic acid Schiff (PAS)-positive granules or vesicles in the immature enterocytes.
2024-11-25 | Congenital diarrhoea due to microvillus inclusion disease: a case report
Inherited diarrheal diseases are group of disorders which cause significant morbidity with dependence on parental nutrition. Microvillus inclusion disease (MVID) is a secretory enteropathy with autosomal recessive inheritance associated with bi allelic mutations in MYO5B gene or more rarely STX3 gene. We report a newborn, which developed diarrhea since birth and whose exome sequencing showed the rare mutation of biallelic STX3. There is a possibility of familial involvement (two other siblings having similar symptoms involved, but not evaluated and died) in this particular case. All three had antenatal polyhydramnios and dilated bowel loops. This case report describes an infant diagnosed with congenital diarrhea due to a genetic mutation, explores the diagnostic process, and outlines the management strategies and outcomes. The report emphasizes the importance of early diagnosis and tailored treatment in improving patient outcomes.
cell therapies
2024-09-01 | 245.9: Adult intestinal transplant program at King Faisal specialist hospital and research center, Riyadh, KSA.
Introduction: Worldwide there still is limited access to transplantation for patients suffering of intestinal failure with TPN associated complications. Despite favorable and improving outcomes there are still reluctancies to answer the obvious need for intestinal transplantation. Methods: An intestinal transplant program was started at King Faisal Hospital and Research Center in Riyadh, Kingdom of Saudi Arabia in October 2017. A total of 11 adult intestinal transplants (ITX) have been performed in 11 recipients with a follow up of 2.8 years. The outcomes herein were analyzed retrospectively by a prospectively designed database. Results: Mean recipient age at time of transplant was 25 years for 6 male and 5 female recipients. Mean duration of total parenteral nutrition (TPN) prior ITX amounted to 34 months. Underlying disease was surgical short bowel syndrome in 5 patients. An additional 5 recipients were transplanted for intestinal motility disorder and 1 for microvillous inclusion disease. In case of intestinal failure associated liver disease (IFALD) pre-transplant liver biopsy was performed in order to rule out irreversible liver pathologies. All patients received a full intestinal allograft including the right hemicolon. Mean cold ischemic times were 218 minutes (range 75-335) and 24 minutes for warm ischaemia (range 17-40). Median length of hospital stay was 61 days (range 21-320). For endoscopic monitoring all recipients received a chimney stoma at the ileal region. All but one patient were discharged without any further TPN nor i.v.- fluid therapy. All of the recipients receiving thymoglobulin induction (n=3) developed biopsy proven rejection within the first year post ITX, whereas only 50% (4 out of 8) did following alemtuzumab induction. Rejections were monitored by protocol biopsies and HLA surveillance. Treatment consisted of steroid pulse, additional antibody administartion (ATG, Alemtuzumab, Infliximab, Vedolizumab, Rituximab), plasma exchange, immunoglobulins or their combination as per nature of the individual rejection. Immunosuppressive maintenance consisted of FK 506/steroids for the first 6 weeks followed by FK 506/mTor inhibition after stoma closure +-steroid withdrawal. 1-, 3- and 5-year survival are 91, 64 and 64 percent. Patient death were sepsis in 2 recipients following non-compliance induced rejections at 8 and 18, self-induced i.v. overdosing for 1 at 18 and a septic shock at 12. Death censored allograft survival was 100%. Average BMI increased from 18 before to 20 one year post transplant. GvHD and PTLD incidence was 0%. 2 recipients developed severe CMV disease with CMV enteritis, being resolved following intensified management. Conclusion: ITX provides a challenging but valuable and life-changing therapeutical option for patients suffering of intestinal failure. It should be considered timely to avoid progression of IFALD with the necessity for combined liver and intestinal or multivisceral transplantation.
2023-01-13 | TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration
SUMMARY The adult gut epithelium has a remarkable ability to recover from damage. To achieve cellular therapies aimed at restoring and/or replacing defective gastrointestinal tissue, it is important to understand the natural mechanisms of tissue regeneration. We employed a combination of high throughput sequencing approaches, mouse genetic models, and murine and human organoid models, and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. Depletion of macrophages or genetic disruption of TGFB-signaling significantly impaired the regenerative response following irradiation. Murine intestinal regeneration is also characterized by a process where a fetal transcriptional signature is induced during repair. In organoid culture, TGFB1-treatment was necessary and sufficient to induce a transcriptomic shift to the fetal-like/regenerative state. The regenerative response was enhanced by the function of mesenchymal cells, which are also primed for regeneration by TGFB1. Mechanistically, integration of ATAC-seq, scRNA-seq, and ChIP-seq suggest that a regenerative YAP-SOX9 transcriptional circuit is activated in epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for the application of the TGFB-induced regenerative circuit in cellular therapy. GRAPHIC ABSTRACT
2021-07-26 | Microvillus Inclusion Disease: Can Mesenchymal Stem Cells Be a Potential Treatment Option?
Microvillus inclusion disease (MVID; MIM #251850), is a rare life-threatening secretory and malabsorptive diarrhea of infancy due to mutations in the MYO5B gene.A 6-day-old male patient was referred to our neonatal intensive care unit for profuse diarrhea beginning on the 2nd day of life causing 17% weight loss, metabolic acidosis and hyponatremia.Our patient had a homozygous mutation in the MYO5B gene.On 110th day of life, mesenchymal stem cell treatment (1x106 cells trans duodenal and 2x106 cells intravenous) was administered.Although fluid and electrolyte requirements did not decrease after stem cell therapy, the rate of blood stream infections was reduced.Small bowel transplantation using cadaveric intestine was performed at the age of 20 months.Unfortunately, the infant died of sepsis one month after transplantation.In this case report, results of stem cell therapy in a newborn infant with MVID were presented and discussed with the relevant literature.
2019-06-01 | GP248 Mesenchymal stem cell therapy in microvillus inclusion disease
Microvillus inclusion disease (MVID; MIM #251850), is a rare life-threatening secretory and malabsorptive diarrhea of infancy due to mutations in the Myosin 5B (MYO5B) gene. Most of the patients die before achieving the opportunity of bowel transplantation due to electrolytes and renal tubular function disturbances and complications of parenteral nutrition. In this case report, results of stem cell therapy in a newborn infant with MVID were presented and discussed with the relevant literature. A 6-day-old male patient was referred to our NICU for profuse diarrhea beginning on the postnatal 2nd day after birth, metabolic acidosis and hyponatremia. He was born at 36+4 gestational weeks as the fourth child of nonconsanguineous parents. Second and third siblings died at 2 and 3,5 months due to complications of intractable diarrhea. Third child's exom sequencing identified a homozygous, disease-causing nonsense variant C.4399C>T (p.Gin1467*) in the MYO5B gene. Both parents were heterozygous for the mutation and they did not accept prenatal diagnosis. Our patient was also affected by homozygous mutation in MYO5B gene. With the knowledge of past history, total parenteral nutrition was started and maximum effort was directed to maintain fluid and electrolyte equilibrium. Patient had high fluid (350 ml/kg/day), sodium (20–25 meq/kg/day) and bicarbonate requirements (12–18 meq/kg/day). On 110th day of life mesenchymal stem cells (1x106 Ü transduodenal and 2x106 Ü IV) were administered. Although fluid and electrolyte requirements did not decrease after 2 months of follow up after stem cell therapy, the rate of blood stream infections was reduced. In MVID, mutations in the MYO5B gene which encodes a protein called myosin Vb contribute to the dysfunction of enterocytes. Survival rate is less than 25% at the age of 9 months. Mortality rate is also high after bowel transplantation. Recently, stem cell therapy was presented as a promising alternative strategy for overcoming the current limitations of intestinal failure treatment. We concluded that, the reason why our patient did not benefit from the treatment was rapid turnover of the intestine epithelial cells and the lack of receptive surface caused by the genetic defect. Furthermore, using modified intestinal stem cells instead of mesenchymal stem cells may be more beneficial. In our patient, decreased incidence of infection with probable immunomodulatory effects of stem cells was the secondary gain.
2016-10-18 | The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.
Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.
small molecules
2026-07-17 | Long-term clinical trajectory of microvillus inclusion disease associated with STXBP2-related familial hemophagocytic lymphohistiocytosis type 5: A case report.
Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin-binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long-term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22-year-old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long-term follow-up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long-term extrahematopoietic phenotype of STXBP2-related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.
2026-05-20 | The UNC45A–MYO5B Axis in Enterohepatic Disorders
Defects in epithelial polarity and apical trafficking underlie a spectrum of rare enterohepatic disorders, including microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC/PFIC). This thesis investigates the molecular relationship between the myosin co-chaperone UNC45A and the motor protein MYO5B, two proteins associated with overlapping intestinal and hepatic phenotypes.
Using intestinal epithelial and hepatocellular models, this work demonstrates that UNC45A is required for MYO5B protein stability and proper Rab11A-dependent apical recycling trafficking. Loss of UNC45A disrupts epithelial polarity, impairs microvillus formation, and induces MVID-like cellular defects. Mechanistic studies further show that specific UNC45A variants impair protein stability and chaperone-associated trafficking pathways. In addition, this thesis explores the pathogenesis of MYO5B-associated cholestasis and evaluates the therapeutic potential of ileal bile acid transporter inhibition in UNC45A-associated cholestatic disease.
Together, these findings establish a functional UNC45A–MYO5B axis linking rare enteropathic and cholestatic disorders at the molecular level and provide new insights into the regulation of epithelial polarity and apical membrane trafficking in the enterohepatic system.
2026-03-30 | Microvillus inclusion disease-associated MYO5B deficiency impairs endosome-to-mitochondrion iron transfer.
MYO5B deficiency causes microvillus inclusion disease (MVID), characterized by the inability to absorb dietary nutrients and secretory diarrhea. MVID intestinal tissue shows metabolic abnormalities, but the causality with MYO5B and the underlying mechanism are unknown. The aim of this study was to determine the effects of MYO5B deficiency on mitochondria as key regulators of cellular metabolism and the underlying mechanism. Intestinal tissue from MVID patients and inducible intestine-specific myo5b-knockout (KO) mouse were examined by using light and large-scale scanning transmission electron microscopy. CRISPR-Cas9 was used to generate MYO5B KO intestinal Caco2 cells. Site-directed mutagenesis was performed to generate MYO5B mutants. Fluorescence-based indicators of mitochondrial membrane potential and iron levels, analyses of carbonylated protein residues from isolated mitochondria, and high-resolution respirometry were used to assess mitochondrial homeostasis and function. MYO5B-deficient Caco2 cells showed fragmented and swollen mitochondria, reduced intra-mitochondrial cristae, defective aerobic respiration, reduced mitochondrial membrane potential, and increased mitochondrial oxidative stress. Introduction of a myc-tagged full-length MYO5B in MYO5B KO cells restored membrane potential, whereas the MVID-causing MYO5B-p.(Pro660Leu) variant and the MYO5B-p.(Lys1534Ala) and -p.(Leu1597Pro) mutants did not, demonstrating causality. Quantitative 3D fluorescence microscopy revealed close associations between mitochondria and MYO5B-positive endosomes carrying the iron-transporting transferrin. Associations between transferrin-loaded endosomes and mitochondria were diminished in MYO5B-depleted Caco2 cells. MYO5B-deficient Caco2 cells showed reduced mitochondrial iron content and an accumulation of iron in the endosomal system. MYO5B deficiency impairs endosome-to-mitochondrial iron transfer, leading to mitochondrial dysfunction. These results offer a novel therapeutic avenue aimed at restoring mitochondrial function in MVID.
2025-12-08 | Microvillus Inclusion Disease: Successful Treatment of Severe Hyponatremia With High-Dose Fludrocortisone via a Possible Gut-Mediated Mechanism.
Microvillus inclusion disease (MVID) is a rare congenital enteropathy marked by severe secretory diarrhea and malabsorption due to microvillous atrophy secondary to accumulation of secretory granules in the apical cytoplasm of enterocytes. Management is supportive with parenteral nutrition and emergent management of acute electrolyte disturbances. We report an 8-month-old male infant with genetically confirmed MVID (MYO5B mutation) who developed life-threatening hyponatremia (serum sodium 118 mmol/L) despite maximal sodium supplementation (>300 mmol/d = 49 mmol/kg/d) and negligible urinary sodium level. High-dose fludrocortisone (100 mcg bid; 28.4 mcg/kg/d) successfully restored serum sodium levels and reduced stool output, with normalization of renin and aldosterone, without adverse effects. This case demonstrates a potential therapeutic benefit of gastrointestinal mineralocorticoid receptor agonism in managing severe hyponatremia in patients with MVID during periods of acute decompensation.
2025-04-30 | LPAR5 as a prospective therapeutic target for treating microvillus inclusion disease
1. Microvillus inclusion disease (MVID) is a rare congenital diarrheal disorder that typically presents within the first week of life manifesting in severe dehydration and malnutrition. The small i...
gene therapies
2026-08-12 | Enterocyte trafficking proteins and the pathophysiological consequences of their sortopathies
Abstract Objective We synthesised current evidence on enterocyte trafficking proteins and elucidated the molecular mechanisms by which their dysfunction contributes to intestinal disease. Methods Search was conducted in PubMed/MEDLINE, Web of Science, and Wiley Online Library for studies published between January 2000 and March 2026, following PRISMA 2020 guidelines. Studies involving enterocyte trafficking proteins were included based on predefined PICO criteria. Results Thirty-six studies were included, identifying key trafficking regulators, including Rab8a, Rab11a, MYO5B, MYO1A, MYO6, syntaxin 3, MUNC18-2, and SNX27, as essential for enterocyte protein sorting and polarity. Six major mechanisms of dysfunction were observed, involving defects in protein maturation, vesicle formation, Rab-mediated trafficking, SNARE-dependent fusion, motor-driven transport, and endosomal recycling. These disruptions converge into three main pathological processes: impaired apical delivery, defective endocytic retrieval, and failed exocytic fusion, ultimately leading to severe congenital enteropathies such as microvillus inclusion disease, chylomicron retention disease, and STXBP2-associated enteropathy. Conclusion Enterocyte trafficking proteins are fundamental determinants of epithelial polarity and intestinal function. Their dysfunction drives a spectrum of severe intestinal disorders through converging mechanisms of protein mislocalisation and barrier disruption. Advancing diagnostic approaches and developing targeted therapies aimed at restoring intracellular trafficking pathways represent critical priorities for improving patient outcomes.
2022-04-11 | A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy
UNC45A is a myosin (co-)chaperone, and mutations in the UNC45A gene were recently identified in osteo-oto-hepato-enteric (O2HE) syndrome patients presenting with congenital diarrhea and intrahepatic cholestasis. Congenital diarrhea and intrahepatic cholestasis are also the prime symptoms in patients with microvillus inclusion disease (MVID) and mutations in MYO5B, encoding the recycling endosome-associated myosin Vb. The aim of this study was to determine whether UNC45A and myosin Vb are functionally linked.CRISPR-Cas9 gene editing and site-directed mutagenesis were performed with intestinal epithelial and hepatocellular cell lines, followed by Western blotting, quantitative polymerase chain reaction, and scanning electron and/or confocal fluorescence microscopy to determine the relationship between (mutants of) UNC45A and myosin Vb.UNC45A depletion in intestinal and hepatic cells reduced myosin Vb protein expression, and in intestinal epithelial cells, it affected 2 myosin Vb-dependent processes that underlie MVID pathogenesis: rat sarcoma-associated binding protein (RAB)11A-positve recycling endosome positioning and microvilli development. Reintroduction of UNC45A in UNC45A-depleted cells restored myosin Vb expression, and reintroduction of UNC45A or myosin Vb, but not the O2HE patient UNC45A-c.1268T>A variant, restored recycling endosome positioning and microvilli development. The O2HE patient-associated p.V423D substitution, encoded by the UNC45A-c.1268T>A variant, impaired UNC45A protein stability but as such not the ability of UNC45A to promote myosin Vb expression and microvilli development.A functional relationship exists between UNC45A and myosin Vb, thereby connecting 2 rare congenital diseases with overlapping enteropathy at the molecular level. Protein instability rather than functional impairment underlies the pathogenicity of the O2HE syndrome-associated UNC45A-p.V423D mutation.
2021-02-17 | Editing Myosin VB Gene to Create Porcine Model of Microvillus Inclusion Disease, With Microvillus-Lined Inclusions and Alterations in Sodium Transporters.
Microvillus inclusion disease (MVID) is caused by inactivating mutations in the myosin VB gene (MYO5B). MVID is a complex disorder characterized by chronic, watery, life-threatening diarrhea that usually begins in the first hours to days of life. We developed a large animal model of MVID to better understand its pathophysiology. Pigs were cloned by transfer of chromatin from swine primary fetal fibroblasts, which were edited with TALENs and single-strand oligonucleotide to introduce a P663-L663 substitution in the endogenous swine MYO5B (corresponding to the P660L mutation in human MYO5B, associated with MVID) to fertilized oocytes. We analyzed duodenal tissues from patients with MVID (with the MYO5B P660L mutation) and without (controls), and from pigs using immunohistochemistry. Enteroids were generated from pigs with MYO5B(P663L) and without the substitution (control pigs). Duodenal tissues from patients with MVID lacked MYO5B at the base of the apical membrane of intestinal cells; instead MYO5B was intracellular. Intestinal tissues and derived enteroids from MYO5B(P663L) piglets had reduced apical levels and diffuse subapical levels of sodium hydrogen exchanger 3 and SGLT1, which regulate transport of sodium, glucose, and water, compared with tissues from control piglets. However, intestinal tissues and derived enteroids from MYO5B(P663L) piglets maintained CFTR on apical membranes, like tissues from control pigs. Liver tissues from MYO5B(P663L) piglets had alterations in bile salt export pump, a transporter that facilitates bile flow, which is normally expressed in the bile canaliculi in the liver. We developed a large animal model of MVID that has many features of the human disease. Studies of this model could provide information about the functions of MYO5B and MVID pathogenesis, and might lead to new treatments.
2019-12-05 | Recent advances in understanding and managing malabsorption: focus on microvillus inclusion disease
Microvillus inclusion disease (MVID) is a rare congenital severe malabsorptive and secretory diarrheal disease characterized by blunted or absent microvilli with accumulation of secretory granules and inclusion bodies in enterocytes. The typical clinical presentation of the disease is severe chronic diarrhea that rapidly leads to dehydration and metabolic acidosis. Despite significant advances in our understanding of the causative factors, to date, no curative therapy for MVID and associated diarrhea exists. Prognosis mainly relies on life-long total parenteral nutrition (TPN) and eventual small bowel and/or liver transplantation. Both TPN and intestinal transplantation are challenging and present with many side effects. A breakthrough in the understanding of MVID emanated from seminal findings revealing mutations inMYO5Bas a cause for MVID. During the last decade, many studies have thus utilized cell lines and animal models with knockdown ofMYO5Bto closely recapitulate the human disease and investigate potential therapeutic options in disease management. We will review the most recent advances made in the research pertaining to MVID. We will also highlight the tools and models developed that can be utilized for basic and applied research to increase our understanding of MVID and develop novel and effective targeted therapies.
2015-07-23 | Myo5b knockout mice as a model of microvillus inclusion disease
Abstract Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b . Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.
proteins
2026-02-12 | Myosin 5b deficiency alters liver proliferation, zonation, and bile acid composition.
Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b's role in the intestine is well characterized, its function in the liver remains unclear. To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
2025-07-30 | Microvillus inclusion disease: a short review of literature.
Microvillus inclusion disease (MVD) is a rare autosomal recessive disease that was first discovered in 1978 by Davidson et al., with significant mortality and morbidity within the first year of life. It presents mainly with abdominal symptoms like diarrhoea, abdominal distension, vomiting electrolyte imbalance. Sometimes, depending on the genetic mutation involved, the phenotypic manifestation can vary. Certain genetic mutations are associated with cholestasis, dilated bowel loops, and metabolic acidosis, whereas some present with nystagmus and reduced visual acuity. Electron microscopy of the duodenal biopsy sample is used as a diagnostic tool. Absence or shortening of apical microvilli with microvillus inclusion bodies in mature enterocytes, which are pathognomonic to MVD alongside periodic acid Schiff (PAS)-positive granules or vesicles in the immature enterocytes.
2024-11-25 | Congenital diarrhoea due to microvillus inclusion disease: a case report
Inherited diarrheal diseases are group of disorders which cause significant morbidity with dependence on parental nutrition. Microvillus inclusion disease (MVID) is a secretory enteropathy with autosomal recessive inheritance associated with bi allelic mutations in MYO5B gene or more rarely STX3 gene. We report a newborn, which developed diarrhea since birth and whose exome sequencing showed the rare mutation of biallelic STX3. There is a possibility of familial involvement (two other siblings having similar symptoms involved, but not evaluated and died) in this particular case. All three had antenatal polyhydramnios and dilated bowel loops. This case report describes an infant diagnosed with congenital diarrhea due to a genetic mutation, explores the diagnostic process, and outlines the management strategies and outcomes. The report emphasizes the importance of early diagnosis and tailored treatment in improving patient outcomes.
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Drug Discovery Landscape
5 orphan drug designations for Microvillus inclusion disease.
5 orphan drug designations for Microvillus inclusion disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
crofelemer | small molecules | FDA | 2023-02-27 | — | Napo Pharmaceuticals Inc. |
Crofelemer | small molecules | EMA | 2022-10-11 | — | Napo Therapeutics S.p.A. |
Retinyl Palmitate, Alisitol (herbal extract), Zn Gluconate | small molecules | FDA | 2021-03-18 | — | Dmitry V. Kravtsov, M.D. |
Alisitol, retinol palmitate, zinc gluconate | small molecules | EMA | 2020-11-13 | — | Vanessa Research Spain S.L. |
racecadotril | small molecules | FDA | 2020-04-13 | — | RNR BioMedical Inc. |
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