A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia.
Adolescent
Adult
Aged
Bone and Bones
/ diagnostic imaging
Cartilage Oligomeric Matrix Protein
/ chemistry
Child
Family
Female
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Models, Molecular
Mutation
Osteochondrodysplasias
/ diagnosis
Pedigree
Phenotype
Protein Conformation
Structure-Activity Relationship
Exome Sequencing
Young Adult
Cartilage oligomeric matrix protein (COMP)
Femoral head necrosis
Multiple epiphyseal dysplasia
Whole-exome sequencing
Journal
BMC medical genetics
ISSN: 1471-2350
Titre abrégé: BMC Med Genet
Pays: England
ID NLM: 100968552
Informations de publication
Date de publication:
27 05 2020
27 05 2020
Historique:
received:
02
02
2020
accepted:
30
04
2020
entrez:
29
5
2020
pubmed:
29
5
2020
medline:
3
11
2020
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32460719
doi: 10.1186/s12881-020-01040-y
pii: 10.1186/s12881-020-01040-y
pmc: PMC7251693
doi:
Substances chimiques
COMP protein, human
0
Cartilage Oligomeric Matrix Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115Subventions
Organisme : The National Natural Science Foundation of China
ID : 81822030
Pays : International
Organisme : The National Natural Science Foundation of China
ID : 81772299
Pays : International
Organisme : Key Technologies Research and Development Program (CN)
ID : 2018YFC0910500
Pays : International
Organisme : CAMS Initiative Fund for Medical Sciences
ID : 2016-I2M-3-003
Pays : International
Organisme : CAMS Initiative Fund for Medical Sciences
ID : 2017-I2M-2-001
Pays : International
Organisme : Beijing Natural Science Foundation
ID : 7191007
Pays : International
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