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1.
J Hum Genet ; 63(7): 851-855, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29703962

ABSTRACT

3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency.


Subject(s)
Abnormalities, Multiple/genetics , Amino Acid Metabolism, Inborn Errors/genetics , Mutation , Syndactyly/genetics , Thiolester Hydrolases/deficiency , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/enzymology , Abnormalities, Multiple/pathology , Adult , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Amino Acid Metabolism, Inborn Errors/enzymology , Amino Acid Metabolism, Inborn Errors/pathology , Base Sequence , Female , Gene Expression , Genes, Recessive , Genetic Association Studies , Humans , Infant , Male , Pedigree , RNA Splicing , Syndactyly/diagnostic imaging , Syndactyly/enzymology , Syndactyly/pathology , Thiolester Hydrolases/genetics , Exome Sequencing
2.
Cell Cycle ; 15(5): 678-88, 2016.
Article in English | MEDLINE | ID: mdl-27104747

ABSTRACT

CDK10/CycM is a protein kinase deficient in STAR (toe Syndactyly, Telecanthus and Anogenital and Renal malformations) syndrome, which results from mutations in the X-linked FAM58A gene encoding Cyclin M. The biological functions of CDK10/CycM and etiology of STAR syndrome are poorly understood. Here, we report that deficiency of CDK10/Cyclin M promotes assembly and elongation of primary cilia. We establish that this reflects a key role for CDK10/Cyclin M in regulation of actin network organization, which is known to govern ciliogenesis. In an unbiased screen, we identified the RhoA-associated kinase PKN2 as a CDK10/CycM phosphorylation substrate. We establish that PKN2 is a bone fide regulator of ciliogenesis, acting in a similar manner to CDK10/CycM. We discovered that CDK10/Cyclin M binds and phosphorylates PKN2 on threonines 121 and 124, within PKN2's core RhoA-binding domain. Furthermore, we demonstrate that deficiencies in CDK10/CycM or PKN2, or expression of a non-phosphorylatable version of PKN2, destabilize both the RhoA protein and the actin network architecture. Importantly, we established that ectopic expression of RhoA is sufficient to override the induction of ciliogenesis resulting from CDK10/CycM knockdown, indicating that RhoA regulation is critical for CDK10/CycM's negative effect on ciliogenesis. Finally, we show that kidney sections from a STAR patient display dilated renal tubules and abnormal, elongated cilia. Altogether, these results reveal CDK10/CycM as a key regulator of actin dynamics and a suppressor of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling. Moreover, they suggest that STAR syndrome is a ciliopathy.


Subject(s)
Actins/metabolism , Anal Canal/abnormalities , Cilia/physiology , Cyclin-Dependent Kinases/physiology , Hypertelorism/enzymology , Kidney/abnormalities , Syndactyly/enzymology , Toes/abnormalities , Urogenital Abnormalities/enzymology , Actins/ultrastructure , Anal Canal/enzymology , Cell Line , Enzyme Stability , Humans , Hypertelorism/genetics , Kidney/enzymology , Phosphorylation , Protein Kinase C/metabolism , Protein Processing, Post-Translational , Signal Transduction , Syndactyly/genetics , Urogenital Abnormalities/genetics , rhoA GTP-Binding Protein/metabolism
3.
Nat Med ; 17(12): 1657-62, 2011 Nov 27.
Article in English | MEDLINE | ID: mdl-22120178

ABSTRACT

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 Ca(v)1.2 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 (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.


Subject(s)
Calcium Signaling , Induced Pluripotent Stem Cells/cytology , Long QT Syndrome/physiopathology , Neurons/cytology , Syndactyly/physiopathology , Tyrosine 3-Monooxygenase/genetics , Autistic Disorder/genetics , Autistic Disorder/physiopathology , Calcium Channels, L-Type/genetics , Calcium Channels, L-Type/metabolism , Calcium Signaling/drug effects , Cell Differentiation , Cell Line , Dopamine/metabolism , Gene Expression Regulation , Humans , Long QT Syndrome/enzymology , Microarray Analysis , Neurons/drug effects , Neurons/metabolism , Norepinephrine/metabolism , Phenotype , Purines/pharmacology , Roscovitine , Syndactyly/enzymology , Tyrosine 3-Monooxygenase/metabolism
4.
Eur J Hum Genet ; 15(7): 743-51, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17440500

ABSTRACT

Here, we report a patient with a novel brachydactyly-syndactyly syndrome and a de novo translocation 46,XY,t(4;6)(q12;p23). We mapped the breakpoint and identified genes in the breakpoint region. One of the genes on chromosome 6, the membrane-associated O-acetyl transferase gene 1 (MBOAT1), was disrupted by the breakpoint. This gene consists of 13 exons and encodes a protein of 495 amino acids. MBOAT1 is predicted to be a transmembrane protein and belongs to the superfamily of membrane-bound O-acyltransferases. These proteins transfer organic compounds, usually fatty acids, onto hydroxyl groups of membrane-embedded targets. Identification of the transferred acyl group and the target may reveal the signaling pathways altered in this novel brachydactyly-syndactyly syndrome.


Subject(s)
Acetyltransferases/genetics , Chromosomes, Human, Pair 4/genetics , Chromosomes, Human, Pair 6/genetics , Hand Deformities, Congenital/genetics , Syndactyly/genetics , Translocation, Genetic , Adult , Fingers/abnormalities , Hand Deformities, Congenital/enzymology , Humans , In Situ Hybridization, Fluorescence , Male , Membrane Proteins , Syndactyly/enzymology
5.
Mamm Genome ; 8(12): 879-83, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9383278

ABSTRACT

The dominant mouse mutation Fused toes is characterized by partial syndactyly of the limbs and thymic hyperplasia. Both morphological abnormalities were shown to be related to impaired regulation of programmed cell death. Ft/Ft embryos die in midgestation showing severe malformations of fore- and midbrain as well as randomized situs. In Ft mice a large chromosomal deletion (about 300 kb) occurred after insertional mutagenesis. In this report we describe the identification of the first gene that has been mutated by Fused toes. The expression of the novel gene Ft1 is reduced in Ft/+ mice and completely absent in Ft/Ft embryos. Analysis of the Ft1 cDNA revealed an open reading frame that could code for a 32-kDa protein with similarities to ubiquitin-conjugating enzymes. Ft1 transcripts with alternative 5' UTR sequences as well as differential usage of polyadenylation sites were found. Interestingly, the 3' parts of the longest Ft1 transcripts are identical to the reverse complement of the 3'-most sequences of the Rb-related p130 gene. Both genes are transcribed in opposite directions and overlap in their 3' UTRs. Despite the close linkage, p130 expression appeared not to be affected by the Ft mutation. In wild type mice, Ft1 expression levels were found to be high in brain, kidney, and testes and detectable in all other adult organs and throughout embryonic development. Finally, we show that Ft1 is conserved among mammals and identify the human homolog.


Subject(s)
Abnormalities, Multiple/genetics , Brain/abnormalities , Mice, Mutant Strains/genetics , Proteins/genetics , Syndactyly/genetics , Thymus Gland/abnormalities , Adaptor Proteins, Signal Transducing , Amino Acid Sequence , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis Regulatory Proteins , Base Sequence , Chromosome Mapping , DNA, Complementary/genetics , Dexamethasone/pharmacology , Embryonic and Fetal Development/genetics , Fetal Heart/physiology , Gene Expression , Genes , Genes, Dominant , Genes, Overlapping , Humans , Hyperplasia , Mice , Molecular Sequence Data , Morphogenesis/genetics , Open Reading Frames , Phenotype , Phosphoproteins/genetics , Retinoblastoma-Like Protein p130 , Sequence Alignment , Sequence Homology, Amino Acid , Syndactyly/enzymology , T-Lymphocytes/drug effects , T-Lymphocytes/pathology , Tail/embryology , Thymus Gland/pathology
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