Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia.

ABSTRACT: Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

SUBMITTER: Guo BB

PROVIDER: S-EPMC7960025 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia.

Guo Bing-Bing BB Jin Jie-Yuan JY Yuan Zhuang-Zhuang ZZ Zeng Lei L Xiang Rong R

BioMed research international 20210308

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study ...[more]

PMID: 33748277

Similar Datasets

A novel COMP mutation in a pseudoachondroplasia family of Chinese origin.

Project description:BackgroundPseudoachondroplasia (PSACH) is caused exclusively by mutations in the gene for cartilage oligomeric matrix protein (COMP). Only a small number of studies have documented the clinical phenotype and genetic basis in Chinese PSACH patients.Case presentationWe investigated a four-generation PSACH pedigree of Chinese Han origin. Two patients and two unaffected individuals were recruited for clinical evaluation and molecular genetic analysis. The genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction (PCR) was adopted to amplify the 8-19 exons of COMP gene. Then the products were sequenced bi-directionally for screening mutation. Clinical evaluation revealed that PSACH patients in this pedigree had a severe disproportionate short stature (-10SD). A heterozygous TGTCCCTGG insertion in exon 13, between nucleotide 1352T and 1353G, were identified in the patients except the unaffected individuals, which resulted in a three-amino-acid insertion (451V_452P ins VPG) in the sixth calmodulin-like repeat of the COMP protein.ConclusionThis c. 1352_1353ins TGTCCCTGG is a novel mutation responsible for severe familial PSACH.

| S-EPMC3119180 | biostudies-literature

A novel mutation in exon 11 of COMP gene in a Chinese family with pseudoachondroplasia.

Project description:Pseudoachondroplasia (PSACH) is a relatively common skeletal dysplasia characterized by disproportionate short stature, joint laxity, early-onset osteoarthrosis, and dysplasia of the spine, epiphysis, and metaphysis. It is known as an autosomal dominant disease which results exclusively from mutations in the gene for Cartilage Oligomeric Matrix Protein (COMP). We have identified a five year old Chinese boy who was diagnosed as pseudoachondroplasia according to clinical manifestations and X-ray symptoms. His mother seems like another effected individual because of the apparent short stature. Genomic DNA was extracted from peripheral blood lymphocytes. DNA sequencing analysis of the COMP gene revealed a heterozygous mutation (c.1219 T > C,p.Cys407Arg) in the patient. His mother was also affected with the same genetic change. Mutations in COMP gene is proved to change the Cartilage Oligomeric Matrix Protein. This missense mutation (c.1219 T > C) has not been reported before and it is not belongs to polymorphism sites. Our results extend the spectrum of mutations in COMP gene leading to pseudoachondroplasia.

| S-EPMC6411627 | biostudies-literature

Decreased Plasma COMP and Increased Plasma CTX-II Levels in a Chinese Pseudoachondroplasia Family with Novel COMP Mutation.

Project description:Pseudoachondroplasia (PSACH) is an autosomal dominant osteochondrodysplasia caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Accurate clinical diagnosis of PSACH is sometimes difficult. Here, we identified a novel COMP mutation (c.1675G>A, p.Glu559Lys) in a Chinese PSACH family. We detected the plasma levels of COMP and type II collagen (CTX-II) in the four affected individuals. The results showed the levels of plasma COMP significantly decreased and plasma CTX-II significantly increased in the three PSACH patients with COMP mutation. However, both plasma levels of COMP and CTX-II were not to have found significant difference between the presymptomatic carrier and the age-matched subjects. In vitro analysis and immunofluorescence displayed wild type COMP homogenously expressed in cytoplasm, but mutant proteins were irregularly accumulated inside the HEK-293 cells. Western blot revealed that the quantity of the mutant COMP was more compared to wild type COMP in cells after transfection for 12 hours and 24 hours. Subsequently, 3D structural analysis showed three changes have taken place in secondary structure of the mutant COMP. In conclusion, the novel mutation of COMP may result in intracellular accumulation of the mutant protein. Decreased plasma COMP and increased plasma CTX-II may potentially serve as diagnostic markers of PSACH but may not be applicable in the presymptomatic carrier.

| S-EPMC5591969 | biostudies-literature

Case Report: Whole-exome sequencing identified two novel COMP variants causing pseudoachondroplasia.

Project description:Pseudoachondroplasia (PSACH) is a rare, dominant genetic disorder affecting bone and cartilage development, characterized by short-limb short stature, brachydactyly, loose joints, joint stiffness, and pain. The disorder is caused by mutations in the COMP gene, which encodes a protein that plays a role in the formation of collagen fibers. In this study, we present the clinical and genetic characteristics of PSACH in two Chinese families. Whole-exome sequencing (WES) analysis revealed two novel missense variants in the COMP gene: NM_000095.3: c.1319G>T (p.G440V, maternal) and NM_000095.3: c.1304A>T (p.D435V, paternal-mosaic). Strikingly, both the G440V and D435V mutations were located in the same T3 repeat motif and exhibited the potential to form hydrogen bonds with each other. Upon further analysis using Missense3D and PyMOL, we ascertained that these mutations showed the propensity to disrupt the protein structure of COMP, thus hampering its functioning. Our findings expand the existing knowledge of the genetic etiology underlying PSACH. The identification of new variants in the COMP gene can broaden the range of mutations linked with the condition. This information can contribute to the diagnosis and genetic counseling of patients with PSACH.

| S-EPMC10702128 | biostudies-literature

Two novel mutations of COMP in Japanese boys with pseudoachondroplasia.

Project description:Mutations in the cartilage oligomeric matrix protein (COMP) gene cause both pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Most mutations in COMP are located in the region encoding type 3 thrombospondin like domain (TSP3D). We report two Japanese boys with PSACH who had different novel in-frame deletions in TSP3D. The result recapitulates previous reports in that the in-frame deletions in TSP3D preferentially caused PSACH rather than MED.

| S-EPMC5993830 | biostudies-literature

A novel deleterious mutation in the COMP gene that causes pseudoachondroplasia.

Project description:Pseudoachondroplasia (PSACH) is a rare and severe genetic disease; therefore, an accurate molecular diagnosis is essential for appropriate disease treatment and family planning. Currently, the diagnosis of PSACH is based mainly on family history, physical examination and radiographic evaluation. Genetic studies of patients with PSACH in Chinese populations have been very limited. With the application of next-generation sequencing (NGS), a comprehensive molecular diagnosis of PSACH is now possible. The purpose of this study was to perform comprehensive NGS-based molecular diagnoses for patients with PSACH in China. We investigated the molecular genetics of one suspected PSACH family in this study. The DNA sample from the proband was sequenced using a custom capture panel that included 249 bone disease genes. Variant calls were filtered and annotated using an in-house automated pipeline. Then, we confirmed the variants by Sanger sequencing in three family members. After co-segregation analysis, the variant, c.1160_1162del of the COMP gene, was identified as a novel mutation responsible for this spontaneous form of PSACH.

| S-EPMC4899602 | biostudies-literature

A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia.

Project description:Pseudoachondroplasia (PSACH) results from mutations in cartilage oligomeric matrix protein (COMP) and the p.D469del mutation within the type III repeats of COMP accounts for approximately 30% of PSACH. To determine disease mechanisms of PSACH in vivo, we introduced the Comp D469del mutation into the mouse genome. Mutant animals were normal at birth but grew slower than their wild-type littermates and developed short-limb dwarfism. In the growth plates of mutant mice chondrocyte columns were reduced in number and poorly organized, while mutant COMP was retained within the endoplasmic reticulum (ER) of cells. Chondrocyte proliferation was reduced and apoptosis was both increased and spatially dysregulated. Previous studies on COMP mutations have shown mutant COMP is co-localized with chaperone proteins, and we have reported an unfolded protein response (UPR) in mouse models of PSACH-MED (multiple epiphyseal dysplasia) harboring mutations in Comp (T585M) and Matn3, Comp etc (V194D). However, we found no evidence of UPR in this mouse model of PSACH. In contrast, microarray analysis identified expression changes in groups of genes implicated in oxidative stress, cell cycle regulation, and apoptosis, which is consistent with the chondrocyte pathology. Overall, these data suggest that a novel form of chondrocyte stress triggered by the expression of mutant COMP is central to the pathogenesis of PSACH.

| S-EPMC3320758 | biostudies-literature

A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia.

Project description:BACKGROUND:Multiple epiphyseal dysplasia (MED) is a skeletal disorder characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. At least 66% of the reported autosomal dominant MED (AD-MED) cases are caused by COMP mutations. METHODS:We recruited a four-generation Chinese family with early-onset hip osteoarthritis, flatfoot, brachydactyly, and mild short stature. An assessment of the family history, detailed physical examinations, and radiographic evaluations were performed on the proband and other family members, followed by the performance of whole-exome sequencing (WES). The pathogenicity of the candidate mutation was also analyzed. RESULTS:An AD-MED family with 10 affected members and 17 unaffected members was recruited. The main radiographic findings were symmetrical changes in the dysplastic acetabulum and femoral heads, irregular contours of the epiphyses, a shortened femoral neck, and flatfoot. Lower bone density was also observed in the ankle joints, wrist joints, and knees, as well as irregular vertebral end plates. In the proband, we identified the missense mutation c.1153G > T (p. Asp385Tyr), located in exon 11 of the COMP gene. This mutation was assessed as 'pathogenic' because of its low allele frequency and its high likelihood of co-segregation with disease in the reported family. Sanger sequencing validated the novel heterozygous mutation c.1153G > T (p. Asp385Tyr) in exon 11 of COMP in all affected individuals in the family. CONCLUSIONS:Our results underlined a key role of the Asp385 amino acid in the protein function of COMP and confirmed the pathogenicity of the COMP (c.1153G > T; p. Asp385Tyr) mutation in AD-MED disease. We have therefore expanded the known mutational spectrum of COMP and revealed new phenotypic information for AD-MED.

| S-EPMC7251693 | biostudies-literature

Recurrent Mutation (p.Arg718Pro) in the COMP Gene with Clinical Heterogeneity of Pseudoachondroplasia.

Project description:IntroductionPseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are allelic and caused by mutations in the COMP gene. Other mutations in the genes MMP13, AIFM1, B3GALT6, MATN3, COL9A1, COL9A2, COL9A3, and SLC26A2 have also been associated with evidence of dysplasia in the epiphysis, metaphysis, and spine.Case presentationWe report on the first Mexican patient diagnosed with PSACH. The diagnosis was confirmed by identifying a recurrent heterozygous mutation c.2153G>C (p.Arg718Pro) in the COMP gene using whole-exome sequencing.DiscussionThe anterior spindle-shaped vertebral bodies and severe short stature are not observed in patients carrying p.Arg718Pro, identifying another amino acid site associated with clinical heterogeneity. Reporting new cases with clinical heterogeneity in terms of phenotype plays a crucial role in understanding PSACH and MED pathogenesis. The most important aspect of this presentation is providing a new perspective on a recognized clinical scenario, thus setting the standard for better genetic counseling.

| S-EPMC10521230 | biostudies-literature

Painful locking of the wrist in a patient with pseudoachondroplasia confirmed by COMP mutation.

Project description:We report the case of a 40-year-old woman with pseudoachondroplasia (PSACH), with a heterozygous mutation (c.806A > G, p.Asp269Gly) located in the Type 3 repeats domain of the cartilage oligomeric matrix protein gene, who complained of the unusual symptom of painful locking of the wrist. Her condition was caused by a non-traumatic enlargement of the extensor carpi radialis longus (ECRL) and brevis (ECRB) tendons along with bulbous swelling of the synoviums around them. Surgical treatment resolved these unusual tendon-related symptoms. Repetitive mechanical loading of the wrist in daily activities, including distal intersection tenosynovitis between the extensor pollicis longus tendon and ECRL and ECRB tendons, may have contributed to changes in the structural integrity of the tendons. We should pay more attention to tendon-related symptoms in patients with PSACH.

| S-EPMC5204134 | biostudies-literature