Japanese familial case with metaphyseal dysplasia, Schmid Type caused by the p.T555P mutation in the COL10A1 gene.
Ontology highlight
ABSTRACT:
SUBMITTER: Hasegawa K
PROVIDER: S-EPMC4322291 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
Publications
Japanese familial case with metaphyseal dysplasia, Schmid Type caused by the p.T555P mutation in the COL10A1 gene.
Hasegawa Kosei K Higuchi Yosuke Y Yamashita Miho M Tanaka Hiroyuki H
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 20150101 1
Similar Datasets
Project description: Not available
| S-EPMC4965511 | biostudies-literature
Project description:Schmid-type metaphyseal chondrodysplasia (MIM 156500) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL10A1 gene (MIM 120110) encoding the α1(X) chains of type X collagen. We report an 8-year-old girl with waddling gait, short stature, mild dorsal scoliosis, coxa vara, short lower limbs, bowing of the femurs, genu varum, and metaphyseal fraying and splaying, who is a carrier of a novel heterozygous 2-bp (c.1894_1895dupTA; p.Leu633Thrfs*45) duplication in exon 3 of the COL10A1 gene.
| S-EPMC6528095 | biostudies-literature
Project description:BackgroundSchmid-type metaphyseal chondrodysplasia (SMCD) is a rare autosomal dominant skeletal dysplasia caused by heterozygous mutations in COL10A1, the gene which encodes collagen type X alpha 1 chain. However, its genotype-phenotype relationship has not been fully determined. Subjects and Methods The proband is a 2-year-old boy, born of non-consanguineous Chinese parents. We conducted a systematic analysis of the clinical and radiological characteristics and a follow-up study of the proband. Whole-exome sequencing was applied for the genetic analysis, together with bioinformatic analysis of predicted consequences of the identified variant. A homotrimer model was built to visualize the affected region and predict possible outcomes of this variant. Furthermore, a literature review and genotype-phenotype analysis were performed by online searching all cases with SMCD.ResultsA novel heterozygous variant (NM_000493.4: c.1863_1866delAATG, NP_000484.2: p.(Met622 Thrfs*54)) was identified in COL10A1 gene in the affected child. And it was predicted to be pathogenic by in silico analysis. Protein modeling revealed that the variant was located in the NC1 domain, which was predicted to produce truncated collagen and impair the trimerization of collagen type X alpha 1 chain and combination with molecules in the matrix. Moreover, genotype-phenotype correlation analysis demonstrated that patients with truncating variants or variants in NC1 domain often presented earlier onset and severer symptoms compared with those with non-truncating or variants in non-NC1 domains.ConclusionThe NC1 domain of COL10A1 was proved to be the hotspot region underlying SMCD, patients with variants in NC1 domain were more likely to present severer manifestations at an earlier age.
| S-EPMC8172203 | biostudies-literature
Project description:BackgroundSchmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare.MethodsTwo probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed.ResultsWe found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T > A (p.Phe589Ile)] and [c.1846A > G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix.ConclusionTwo novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.
| S-EPMC6923838 | biostudies-literature
Project description:Heterozygous mutations in COL10A1 lead to metaphyseal chondrodysplasia type Schmid (MCDS), a skeletal disorder characterized by epiphyseal abnormalities. Prior analysis revealed impaired trimerization and intracellular retention of mutant collagen type X alpha 1 chains as cause for elevated endoplasmic reticulum (ER) stress. However, how ER stress translates into structural defects remained unclear. We generated a medaka (Oryzias latipes) MCDS model harboring a 5 base pair deletion in col10a1, which led to a frameshift and disruption of 11 amino acids in the conserved trimerization domain. col10a1Δ633a heterozygotes recapitulated key features of MCDS and revealed early cell polarity defects as cause for dysregulated matrix secretion and deformed skeletal structures. Carbamazepine, an ER stress-reducing drug, rescued this polarity impairment and alleviated skeletal defects in col10a1Δ633a heterozygotes. Our data imply cell polarity dysregulation as a potential contributor to MCDS and suggest the col10a1Δ633a medaka mutant as an attractive MCDS animal model for drug screening.
| S-EPMC10952040 | biostudies-literature
Project description:To evaluate the clinical-phenotypic characteristics of Schmid metaphyseal chondrodysplasia (SMCD) inflicted by a novel missense mutation of COL10A1 gene: c.2020G > A; p.Gly674Arg. A female child aged about 3 yrs. and 8 months was subjected to Radiograph test to validate the symptoms of SMCD. The polymorphism analysis by the next-generation sequencing (NGS) was performed using the peripheral blood DNA samples of the patient and other family inmates, including, the younger male sibling. The effect of the mutation on the non-collagenous carboxyl-terminal (NC1) domain of collagen X was studied using the SWISS-MODEL online server for trimer modelling; PROSA and PROCHECK-Ramachandran plot for structural validation; Mean Square Plot (RMSF) for structural rigidity. Radiograph examination of lower limbs confirmed the bowed legs in both the patient and her younger brother (study groups). The inheritance of the novel missense mutation of COL10A1: c.2020G > A; p.Gly674Arg (at chromosome-6q22.1) was confirmed in the study groups from the SMCD-affected mother. The extended interactions of the mutant-Arg674 with the Ser552 and Phe589 (β strand B) in the NC1 domain of α1(X) chain monomer is more likely to intervene its trimer formation by weakening the structural rigidity of the crucial strand H compared to its wild type. This plausibly deters the collagen X synthesis inflicting the bowed legs with the altered distal ulna bone morphology in the study groups. The inheritance of COL10A1 mutation: c.2020G > A; p.Gly674Arg has inflicted the SMCD with the characteristic bowed legs in the study groups. Radiograph and NGS could be a valid diagnostic module to initiate the treatment of SMCD.
| S-EPMC6950639 | biostudies-literature
Project description:Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation.
| S-EPMC4435711 | biostudies-literature
Project description:Spondylometaphyseal dysplasia (SMD) comprises a heterogeneous group of heritable skeletal dysplasias characterized by modifications of the vertebral bodies of the spine and metaphyses of the tubular bones. The genetic etiology of SMD is currently unknown; however, the type X collagen gene (COL10A1) is considered an excellent candidate, for two reasons: first, Schmid metaphyseal chondrodysplasia, a condition known to result from COL10A1 mutations, shows a significant phenotypic overlap with SMD; and, second, transgenic mice carrying deletions in type X collagen show SMD phenotypes. Hence, we examined the entire coding region of COL10A1 by direct sequencing of DNA from five unrelated patients with SMD and found a heterozygous missense mutation (Gly595Glu) cosegregating with the disease phenotype in one SMD family. This initial documented identification of a mutation in SMD expands our knowledge concerning the range of the pathological phenotypes that can be produced by aberrations of type X collagen (type X collagenopathy).
| S-EPMC1377637 | biostudies-other
Project description:This study aimed to gain a better understanding of the molecular circuitry of Schmid-type metaphyseal chondrodysplasia (SMCD), and to identify more potential genes associated with the pathogenesis of SMCD. Microarray data from GSE72261 were downloaded from the NCBI GEO database, including collagen X p.Asn617Lys knock-in mutation (ColXN617K), ablated XBP1 activity (Xbp1CartΔEx2), compound mutant (C/X), and wild-type (WT) specimens. Differentially expressed genes (DEGs) were screened in Xbp1 vs. WT, Col vs. WT and CX vs. WT, respectively. Pathway enrichment analysis of these DEGs was performed. Transcription factors (TFs) of the overlapping DEGs were identified. Weighted correlation network analysis (WGCNA) was performed to find modules of DEGs with high correlations, followed by gene function analysis and a protein-protein interaction network construction. In total, 481, 1,530 and 1,214 DEGs were identified in Xbp1 vs. WT, Col vs. WT and CX vs. WT, respectively. These DEGs were enriched in different pathways, such as extracellular matrix (ECM)-receptor interaction and metabolism-related pathways. A total of 7 TFs were found to regulate 19 common upregulated genes, and 4 TFs were identified to regulate 21 common downregulated genes. Two significant gene co-expression modules were enriched and DEGs in the 2 modules were mainly enriched in different biological processes, such as ribosome biogenesis. Moreover, Kras (downregulated), Col5a1 (upregulated) and Furin (upregulated) were both identified in the regulatory networks and protein-protein interaction (PPI) network. On the whole, our findings indicate that the Kras, Col5a1 and Furin genes may play essential roles in the molecular mechanisms of SMCD, which warrants further investigation.
| S-EPMC5428963 | biostudies-literature
Project description: Not available
| S-EPMC6073055 | biostudies-literature