RARE DISEASE
Coffin-Lowry syndrome
Coffin-Lowry syndrome
Coffin-Lowry syndrome
Synonyms: CLS
Synonyms: CLS
Synonyms: CLS
Drug discovery
41
papers
On emerging therapies
Overview
Coffin-Lowry syndrome (CLS) is a rare X-linked dominant disorder caused by RPS6KA3 gene mutations, leading to ribosomal protein S6 kinase deficiency. It is characterized by intellectual disability (severe in males, variable in females), distinctive facies (prominent forehead, down-slanting palpebral fissures), skeletal abnormalities (kyphoscoliosis, tapering fingers), and neurological complications like stimulus-induced drop episodes (SIDEs). Multidisciplinary management focuses on supportive therapies, early intervention, and monitoring progressive complications [1][2][6].
Burden
Chronic disability with progressive kyphoscoliosis, cardiac/respiratory complications, and reduced life expectancy (average ~20.5 years) [1][18].
High care demands: Long-term mobility aids, adaptive devices, and surgical interventions [3][7].
Emotional/economic strain on families due to lifelong dependency and complex medical needs [3][18].
Therapies
Multidisciplinary care: Physical, occupational, and speech therapy; anticonvulsants (e.g., sodium oxybate) for SIDEs; orthopedic interventions for spinal/skeletal deformities [3][7][16].
Behavioral/educational support: Individualized education plans (IEPs), applied behavior analysis (ABA) [3].
Genetic counseling: Essential for recurrence risk assessment and family planning [1][3].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neurological diseases
Research Papers
41 drug discovery papers about Coffin-Lowry syndrome. Recent publications:
41 drug discovery papers about Coffin-Lowry syndrome. Recent publications:
categories:
Small molecules
small molecules
2025-10-24 | Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.
The ribosomal protein S6 kinase family members play essential biological functions in disease, from cancer to intellectual disability. Little is known about ribosomal proteins S6 kinase C1 (RPS6KC1), aside from its lack of phosphorylation capacity and its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 (PRDX3) transport to mitochondria. Through whole-exome sequencing, we identified bi-allelic RPS6KC1 variants in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome caused by RPS6KA3 mutations. Functional studies on peripheral blood mononuclear cells (PBMCs) from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and sphingosine kinase 1 (SPHK1), accompanied by marked repression of the mammalian target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K) pathway. We detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Further studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan. These findings underscore the crucial roles of RPS6KC1 in neurodevelopment by controlling ribosomal protein synthesis, lipid signaling, and the mTOR pathway.
2025-03-17 | P448: Identification of a novel RPS6KA3 variant in a female child with features of Coffin-Lowry syndrome: A case study
Treatment and Management: Patient was started on 10 mg biotin daily.Outcome and Follow-Up: Patient is currently undergoing monitoring for improvement in symptoms.Treatment with biotin may reverse many of the ophthalmologic findings and some or all of the myelopathy.Discussion: Late onset biotinidase deficiency may be mistaken for neuromyelitis optica, multiple sclerosis, or an alternative neurogenetic condition.Testing for late onset biotinidase deficiency is fast, inexpensive, and if diagnostic, would result in a significant change in management.Conclusion: Further research is needed on the incidence of late onset biotinidase deficiency in those with clinical diagnoses of neuromyelitis optica and multiple sclerosis.Introduction: Biotinidase deficiency, if not detected on newborn screening, is classically a early childhood onset disorder which may present with seizures, developmental delay, skin rash, alopecia, optic atrophy, hearing loss, and respiratory problems.However, rare instances show late onset in older children, adolescents, or adults with symptoms such as optic atrophy, peripheral neuropathy, myelopathy, spastic paraparesis, recurrent infections, and white matter abnormalities.Case Presentation: Patient is a 33-year-old male with progressive spastic diplegia, bilateral optic atrophy, peripheral neuropathy, neurogenic bladder, and recurrent infectious.White matter abnormalities were present on the MRI of brain and spine.Symptoms began in his twenties.He was previously diagnosed with Neuromyelitis Optica, but treatment was unsuccessful.Extensive workup prior to genetics evaluation was non-diagnostic.
2022-06-09 | Defective synaptic plasticity in a model of Coffin-Lowry Syndrome is rescued by simultaneously targeting PKA and MAPK pathways
ABSTRACT Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a molecular model of Coffin-Lowry Syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. Simultaneous treatment with an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and LTF to a greater extent than either drug alone and greater than their additive effects. Indeed, the combined drugs exerted synergistic effects on both RSK activation and LTF, fully restoring RSK phosphorylation and LTF. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated RSK.
2021-10-28 | Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways.
Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller individual drug 'doses'. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair histone acetylation, L-LTP, and learning.
2020-12-01 | Accelerated tooth movement in Rsk2-deficient mice with impaired cementum formation
Abstract Coffin–Lowry–Syndrome (CLS) is a X-linked mental retardation characterized by skeletal dysplasia and premature tooth loss. We and others have previously demonstrated that the ribosomal S6 kinase RSK2, mutated in CLS, is essential for bone and cementum formation; however, it remains to be established whether RSK2 plays also a role in mechanically induced bone remodeling during orthodontic tooth movement (OTM). We, therefore, performed OTM in wild-type (WT) mice and Rsk2-deficient mice using Nitinol tension springs that were fixed between the upper left molars and the incisors. The untreated contralateral molars served as internal controls. After 12 days of OTM, the jaws were removed and examined by micro-computed tomography (µCT), decalcified histology, and immunohistochemistry. Our analysis of the untreated teeth confirmed that the periodontal phenotype of Rsk2 -deficient mice is characterized by alveolar bone loss and hypoplasia of root cementum. Quantification of OTM using µCT revealed that OTM was more than two-fold faster in Rsk2 -deficient mice as compared to WT. We also observed that OTM caused alveolar bone loss and root resorptions in WT and Rsk2 -deficient mice. However, quantification of these orthodontic side effects revealed no differences between WT and Rsk2 -deficient mice. Taken together, Rsk2 loss-of-function accelerates OTM in mice without causing more side effects.
gene therapies
2026-01-15 | [Case Report of One Family With Coffin-Lowry Syndrome and Literature Review of 28 Cases in China].
To investigate the clinical phenotypes and genotypic characteristics of Chinese patients with Coffin-Lowry syndrome. The clinical data and genetic test results of a family with Coffin-Lowry syndrome were retrospectively analyzed. A literature review was conducted to summarize the clinical characteristics and gene mutation characteristics of patients with Coffin-Lowry syndrome in China. The proband was a 1-year-old boy with distinctive facial features, puffy but tapered fingers, hypotonia, growth retardation, and delayed cognitive and motor development. Genetic analysis revealed a hemizygous c.1603-2A>G mutation in intron 17 of the RPS6KA3 gene in the proband. His mother was a heterozygous carrier. The identified mutation has not been reported previously. The proband's maternal half-brother and half-sister also exhibited similar clinical manifestations and were diagnosed with Coffin-Lowry syndrome together with the proband. The proband was followed up until 3 years and 8 months old, by which time he was not capable of walking steadily independently or speech. Including the 4 members of this family, a total of 28 Chinese patients were identified. Their clinical manifestations included special facial features (100%), cognitive and language/motor developmental delays (92.6%), hypotonia (95.2%), tapered fingers (88.5%), and scoliosis or kyphosis (45%). Genetic sequencing was performed in 24 patients, revealing missense mutations in 3 cases (12.5%), frameshift mutations in 5 cases (20.8%), nonsense mutations in 9 cases (37.5%), splice-site mutations in 4 cases (16.7%), and exon deletions in 2 cases (8.3%). No mutation hotspots were identified. Coffin-Lowry syndrome should be considered in children with cognitive and language/motor developmental delays, distinctive facial features, tapered fingers, and hypotonia. Genetic testing can assist with early diagnosis.
2025-01-29 | Myoclonic reflex and non‐reflex seizures in a female child with Coffin–Lowry syndrome: Clinical vignette
Content available: Video.
2023-06-01 | P-708 Establishment of linkage phase, using Oxford Nanopore Technologies, for Preimplantation Genetic Testing of Coffin-Lowry syndrome with a de novo RPS6KA3 mutation
Abstract Study question There was a challenge to establishing haplotype for PGT in the family with de novo mutation because of the lack of information from affected members. Summary answer The ONT platform combined with MARSALA method can be used to perform PGT for DNM patients without the need for other samples as a reference. What is known already The proband was a 31-year-old female who was born with mental retardation and language delay. On physical examination, she was found to have distinctive Coffin-Lowry Syndrome features, such as distance between the eyes and low nasal bridge. However, the proband’s parents did not show any abnormalities. The couple underwent genetic counseling and whole-exome sequencing (WES). The results showed that a frameshift mutation (c.1496delG, p.Gly499Valfs*25) was identified in the RPS6KA3 gene, with a true mutation in the proband but no mutations in the parents. Study design, size, duration A couple requested genetic counseling at the reproductive center of Zhongshan Boai Hospital and underwent whole-exome sequencing (WES) in 2019. The proband then underwent PGT with Oxford Nanopore Technologies (ONT) and the MARSALA platform to block the transmission of the pathogenic mutation to her offspring in 2022. Participants/materials, setting, methods The proband underwent PGT to block the transmission of the pathogenic mutation to her offspring.We used long-read sequencing on the ONT platform to directly detect the mutation and nearby SNPs for construction of the haplotype in PGT. The MARSALA method was used to detect both the SNP-based haplotype and chromosome copy number variations in each blastocyst. Finally, a normal embryo was selected by comparison to the haplotype of the proband and transferred into the uterus. Main results and the role of chance Using WES, we found the novel, heterozygous, pathogenic c.1496delG (p.Gly499Valfs*25) mutation of the RPS6KA3 gene in the proband. The SNP-based haplotype that was linked to the pathogenic mutation site was successfully established in the proband, without the need for other family members to be tested with ONT. Eight blastocysts were biopsied to perform PGT and were assessed with a haplotype linkage analysis (30 SNP sites selected), to give results that were consistent with direct mutation detection using Sanger sequencing. The results of PGT showed that three of the eight blastocysts were normal, without the DNM. Moreover, the patient had a successful pregnancy, after transfer of a normal blastocyst into the uterus, and delivered a healthy baby. Limitations, reasons for caution This strategy has only been applied to one case and more cases with de novo mutaition are needed to prove the feasibility of this strategy for PGT-M. Wider implications of the findings This study is the first report of a de novo RPS6KA3 c.1496delG mutation in patient with CLS, which can expands the RPS6KA3 mutation spectrum and also provides a new strategy based on ONT and MARSALA to perform PGT-M with DNMs without the need for a pedigree sample as a reference. Trial registration number Not applicable
1999-08-06 | Requirement of Rsk-2 for Epidermal Growth Factor-Activated Phosphorylation of Histone H3
During the immediate-early response of mammalian cells to mitogens, histone H3 is rapidly and transiently phosphorylated by one or more unidentified kinases. Rsk-2, a member of the pp90rsk family of kinases implicated in growth control, was required for epidermal growth factor (EGF)-stimulated phosphorylation of H3. RSK-2 mutations in humans are linked to Coffin-Lowry syndrome (CLS). Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wild-type RSK-2 gene restored EGF-stimulated phosphorylation of H3 in CLS cells. In addition, disruption of the RSK-2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of Rsk-2, suggesting that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression.
small molecules
2025-10-24 | Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.
The ribosomal protein S6 kinase family members play essential biological functions in disease, from cancer to intellectual disability. Little is known about ribosomal proteins S6 kinase C1 (RPS6KC1), aside from its lack of phosphorylation capacity and its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 (PRDX3) transport to mitochondria. Through whole-exome sequencing, we identified bi-allelic RPS6KC1 variants in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome caused by RPS6KA3 mutations. Functional studies on peripheral blood mononuclear cells (PBMCs) from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and sphingosine kinase 1 (SPHK1), accompanied by marked repression of the mammalian target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K) pathway. We detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Further studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan. These findings underscore the crucial roles of RPS6KC1 in neurodevelopment by controlling ribosomal protein synthesis, lipid signaling, and the mTOR pathway.
2025-03-17 | P448: Identification of a novel RPS6KA3 variant in a female child with features of Coffin-Lowry syndrome: A case study
Treatment and Management: Patient was started on 10 mg biotin daily.Outcome and Follow-Up: Patient is currently undergoing monitoring for improvement in symptoms.Treatment with biotin may reverse many of the ophthalmologic findings and some or all of the myelopathy.Discussion: Late onset biotinidase deficiency may be mistaken for neuromyelitis optica, multiple sclerosis, or an alternative neurogenetic condition.Testing for late onset biotinidase deficiency is fast, inexpensive, and if diagnostic, would result in a significant change in management.Conclusion: Further research is needed on the incidence of late onset biotinidase deficiency in those with clinical diagnoses of neuromyelitis optica and multiple sclerosis.Introduction: Biotinidase deficiency, if not detected on newborn screening, is classically a early childhood onset disorder which may present with seizures, developmental delay, skin rash, alopecia, optic atrophy, hearing loss, and respiratory problems.However, rare instances show late onset in older children, adolescents, or adults with symptoms such as optic atrophy, peripheral neuropathy, myelopathy, spastic paraparesis, recurrent infections, and white matter abnormalities.Case Presentation: Patient is a 33-year-old male with progressive spastic diplegia, bilateral optic atrophy, peripheral neuropathy, neurogenic bladder, and recurrent infectious.White matter abnormalities were present on the MRI of brain and spine.Symptoms began in his twenties.He was previously diagnosed with Neuromyelitis Optica, but treatment was unsuccessful.Extensive workup prior to genetics evaluation was non-diagnostic.
2022-06-09 | Defective synaptic plasticity in a model of Coffin-Lowry Syndrome is rescued by simultaneously targeting PKA and MAPK pathways
ABSTRACT Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a molecular model of Coffin-Lowry Syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. Simultaneous treatment with an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and LTF to a greater extent than either drug alone and greater than their additive effects. Indeed, the combined drugs exerted synergistic effects on both RSK activation and LTF, fully restoring RSK phosphorylation and LTF. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated RSK.
2021-10-28 | Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways.
Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller individual drug 'doses'. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair histone acetylation, L-LTP, and learning.
2020-12-01 | Accelerated tooth movement in Rsk2-deficient mice with impaired cementum formation
Abstract Coffin–Lowry–Syndrome (CLS) is a X-linked mental retardation characterized by skeletal dysplasia and premature tooth loss. We and others have previously demonstrated that the ribosomal S6 kinase RSK2, mutated in CLS, is essential for bone and cementum formation; however, it remains to be established whether RSK2 plays also a role in mechanically induced bone remodeling during orthodontic tooth movement (OTM). We, therefore, performed OTM in wild-type (WT) mice and Rsk2-deficient mice using Nitinol tension springs that were fixed between the upper left molars and the incisors. The untreated contralateral molars served as internal controls. After 12 days of OTM, the jaws were removed and examined by micro-computed tomography (µCT), decalcified histology, and immunohistochemistry. Our analysis of the untreated teeth confirmed that the periodontal phenotype of Rsk2 -deficient mice is characterized by alveolar bone loss and hypoplasia of root cementum. Quantification of OTM using µCT revealed that OTM was more than two-fold faster in Rsk2 -deficient mice as compared to WT. We also observed that OTM caused alveolar bone loss and root resorptions in WT and Rsk2 -deficient mice. However, quantification of these orthodontic side effects revealed no differences between WT and Rsk2 -deficient mice. Taken together, Rsk2 loss-of-function accelerates OTM in mice without causing more side effects.
gene therapies
2026-01-15 | [Case Report of One Family With Coffin-Lowry Syndrome and Literature Review of 28 Cases in China].
To investigate the clinical phenotypes and genotypic characteristics of Chinese patients with Coffin-Lowry syndrome. The clinical data and genetic test results of a family with Coffin-Lowry syndrome were retrospectively analyzed. A literature review was conducted to summarize the clinical characteristics and gene mutation characteristics of patients with Coffin-Lowry syndrome in China. The proband was a 1-year-old boy with distinctive facial features, puffy but tapered fingers, hypotonia, growth retardation, and delayed cognitive and motor development. Genetic analysis revealed a hemizygous c.1603-2A>G mutation in intron 17 of the RPS6KA3 gene in the proband. His mother was a heterozygous carrier. The identified mutation has not been reported previously. The proband's maternal half-brother and half-sister also exhibited similar clinical manifestations and were diagnosed with Coffin-Lowry syndrome together with the proband. The proband was followed up until 3 years and 8 months old, by which time he was not capable of walking steadily independently or speech. Including the 4 members of this family, a total of 28 Chinese patients were identified. Their clinical manifestations included special facial features (100%), cognitive and language/motor developmental delays (92.6%), hypotonia (95.2%), tapered fingers (88.5%), and scoliosis or kyphosis (45%). Genetic sequencing was performed in 24 patients, revealing missense mutations in 3 cases (12.5%), frameshift mutations in 5 cases (20.8%), nonsense mutations in 9 cases (37.5%), splice-site mutations in 4 cases (16.7%), and exon deletions in 2 cases (8.3%). No mutation hotspots were identified. Coffin-Lowry syndrome should be considered in children with cognitive and language/motor developmental delays, distinctive facial features, tapered fingers, and hypotonia. Genetic testing can assist with early diagnosis.
2025-01-29 | Myoclonic reflex and non‐reflex seizures in a female child with Coffin–Lowry syndrome: Clinical vignette
Content available: Video.
2023-06-01 | P-708 Establishment of linkage phase, using Oxford Nanopore Technologies, for Preimplantation Genetic Testing of Coffin-Lowry syndrome with a de novo RPS6KA3 mutation
Abstract Study question There was a challenge to establishing haplotype for PGT in the family with de novo mutation because of the lack of information from affected members. Summary answer The ONT platform combined with MARSALA method can be used to perform PGT for DNM patients without the need for other samples as a reference. What is known already The proband was a 31-year-old female who was born with mental retardation and language delay. On physical examination, she was found to have distinctive Coffin-Lowry Syndrome features, such as distance between the eyes and low nasal bridge. However, the proband’s parents did not show any abnormalities. The couple underwent genetic counseling and whole-exome sequencing (WES). The results showed that a frameshift mutation (c.1496delG, p.Gly499Valfs*25) was identified in the RPS6KA3 gene, with a true mutation in the proband but no mutations in the parents. Study design, size, duration A couple requested genetic counseling at the reproductive center of Zhongshan Boai Hospital and underwent whole-exome sequencing (WES) in 2019. The proband then underwent PGT with Oxford Nanopore Technologies (ONT) and the MARSALA platform to block the transmission of the pathogenic mutation to her offspring in 2022. Participants/materials, setting, methods The proband underwent PGT to block the transmission of the pathogenic mutation to her offspring.We used long-read sequencing on the ONT platform to directly detect the mutation and nearby SNPs for construction of the haplotype in PGT. The MARSALA method was used to detect both the SNP-based haplotype and chromosome copy number variations in each blastocyst. Finally, a normal embryo was selected by comparison to the haplotype of the proband and transferred into the uterus. Main results and the role of chance Using WES, we found the novel, heterozygous, pathogenic c.1496delG (p.Gly499Valfs*25) mutation of the RPS6KA3 gene in the proband. The SNP-based haplotype that was linked to the pathogenic mutation site was successfully established in the proband, without the need for other family members to be tested with ONT. Eight blastocysts were biopsied to perform PGT and were assessed with a haplotype linkage analysis (30 SNP sites selected), to give results that were consistent with direct mutation detection using Sanger sequencing. The results of PGT showed that three of the eight blastocysts were normal, without the DNM. Moreover, the patient had a successful pregnancy, after transfer of a normal blastocyst into the uterus, and delivered a healthy baby. Limitations, reasons for caution This strategy has only been applied to one case and more cases with de novo mutaition are needed to prove the feasibility of this strategy for PGT-M. Wider implications of the findings This study is the first report of a de novo RPS6KA3 c.1496delG mutation in patient with CLS, which can expands the RPS6KA3 mutation spectrum and also provides a new strategy based on ONT and MARSALA to perform PGT-M with DNMs without the need for a pedigree sample as a reference. Trial registration number Not applicable
1999-08-06 | Requirement of Rsk-2 for Epidermal Growth Factor-Activated Phosphorylation of Histone H3
During the immediate-early response of mammalian cells to mitogens, histone H3 is rapidly and transiently phosphorylated by one or more unidentified kinases. Rsk-2, a member of the pp90rsk family of kinases implicated in growth control, was required for epidermal growth factor (EGF)-stimulated phosphorylation of H3. RSK-2 mutations in humans are linked to Coffin-Lowry syndrome (CLS). Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wild-type RSK-2 gene restored EGF-stimulated phosphorylation of H3 in CLS cells. In addition, disruption of the RSK-2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of Rsk-2, suggesting that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression.
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