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A de novo CCDC6 inframe deletion inducing phosphoprotein phosphatase dysfunction and arising CLAMP syndrome showing Marfan-like features

ABSTRACT: Phosphoprotein phosphatases are the most abundant in the cell and regulate various cellular functions, such as cell survival, DNA damage response, tau dephosphorylation, and apoptosis. Some phosphoprotein phosphatase dysfunctions promote neurodevelopmental disorders. Exome or genome sequencing identified individuals with Marfan syndrome-like connective tissue disorders, mild neurodevelopmental disorders, and attention deficit in 11 individuals from 10 families due to a de novo in-frame deletion (NM_005436.5:c.415_417del p.Glu139del) in the CCDC6 gene. Zebrafish model analysis revealed loss of sociability and abnormal shapes in the skull, vertebra, and ribs. Proteome analyses using patient-derived lymphoblastoid cell line or mutant or wild-type CCDC6 overexpression in HeLa cells showed mutant CCDC6 strongly binds to phosphoprotein phosphatase and its regulators, causing phosphorylation regulation disorders. Interestingly, these patients showed partially overlapped findings of reported PP2A-related disorders. We demonstrate a new disorder, CLAMP syndrome, Craniofacial dysmorphisms, Language delay, Autistic features, Marfan syndrome-like findings, and Phosphoprotein phosphatase dysfunction.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Naomichi Matsumoto, Hidehisa Takahashi

PROVIDER: PXD064351 | JPOST Repository | Thu May 28 00:00:00 BST 2026

REPOSITORIES: jPOST

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			Action	DRS
	20230830%20LCL%20peptide_Progenesis.csv	Csv
	230825QE_Suzuki_phos_Patient.raw	Raw
	230825QE_Suzuki_phos_control.raw	Raw
	F006178.xml	Xml
	LCL%20CCDC6.mgf	Mgf

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A de novo CCDC6 inframe deletion inducing phosphoprotein phosphatase dysfunction and arising CLAMP syndrome showing Marfan-like features

Project description:Phosphoprotein phosphatases are the most abundant in the cell and regulate various cellular functions, such as cell survival, DNA damage response, tau dephosphorylation, and apoptosis. Some phosphoprotein phosphatase dysfunctions promote neurodevelopmental disorders. Exome or genome sequencing identified individuals with Marfan syndrome-like connective tissue disorders, mild neurodevelopmental disorders, and attention deficit in 11 individuals from 10 families due to a de novo in-frame deletion (NM_005436.5:c.415_417del p.Glu139del) in the CCDC6 gene. Zebrafish model analysis revealed loss of sociability and abnormal shapes in the skull, vertebra, and ribs. Proteome analyses using patient-derived lymphoblastoid cell line or mutant or wild-type CCDC6 overexpression in HeLa cells showed mutant CCDC6 strongly binds to phosphoprotein phosphatase and its regulators, causing phosphorylation regulation disorders. Interestingly, these patients showed partially overlapped findings of reported PP2A-related disorders. We demonstrate a new disorder, CLAMP syndrome, Craniofacial dysmorphisms, Language delay, Autistic features, Marfan syndrome-like findings, and Phosphoprotein phosphatase dysfunction.

2026-05-28 | PXD064339 | JPOST Repository

Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome

Project description:Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca2+) signaling and activity-dependent gene expression and show abnormalities in differentiation. Neurons from individuals with Timothy syndrome show increased expression of markers of the upper cortical layer and decreased expression of callosal projection markers. In addition, the mutation that causes Timothy syndrome leads to an increase in the production of neurons that synthesize norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase and atypical L-type–channel blocker. These findings provide strong evidence that Cav1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome. Total RNA was isolated from control and TS cells: fibroblasts, iPSCs, neurospheres (at day 7 in suspension), neurons at rest (day 45 of differentiation) and neurons kept in 67mM KCl for 9h. For sample titles, D1,D2 and D3 represent independent differentiation experiments. The number after - represents the iPSC cell line number. GSE25542_non-normalized.txt.gz contains data for 5 outliers.

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Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome

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Project description:From a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism carrying a deleterious variant in the EBF3 (Early B-cell Factor 3) gene detected by whole-exome sequencing. Five missense, two nonsense, one 9-bp duplication, and one splice-site variant in EBF3 were found; the mutation occurred de novo in eight individuals, and the missense variant c.625C>T [p.(Arg209Trp)] was inherited by two affected siblings from their healthy mother who is a mosaic. EBF3 belongs to the early B-cell factor family (also known as Olf, COE, or O/E) and encodes a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicts damaging effects of the five amino acid substitutions on DNA-binding of EBF3. Transient expression of EBF3 mutant proteins in HEK 293T cells revealed mislocalization of all but one mutant in the cytoplasm in addition to nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the CDKN1A reporter gene, and EBF3 mutant proteins were less tightly associated with chromatin as demonstrated by in situ subcellular fractionation experiments. Finally, RNA-seq and ChIP-seq experiments demonstrate that EBF3 acts as a transcriptional regulator and EBF3 mutant protein had reduced genome-wide DNA binding and gene regulatory activity. Our findings demonstrate that variants that disrupt EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay, and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders.

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Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

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