Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

Dennis, Ella P.; Greenhalgh‐Maychell, Phillippa L.; Briggs, Michael D.

doi:10.1002/dvdy.221

Cited by 17 publications

(18 citation statements)

References 106 publications

(271 reference statements)

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“…Most mutations of MED that have been reported involve COMP mutations. In addition to COMP, some forms of MED can also be caused by mutations in MATN3, COL9A1, COL9A2, COL9A3, COL2A1, FGFR1, SLC26A2 and DTDST [23][24][25]. In our study, the proband was highly suspected of having PSACH based on the following points: (1) Only the COMP mutation was found as a possible disease-causing gene by WES and cosegregated with the affected family members.…”

Section: Discussionmentioning

confidence: 78%

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

Guo

Jin

Yuan

et al. 2021

BioMed Research International

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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.

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Section: Discussionmentioning

confidence: 78%

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

Guo

Jin

Yuan

et al. 2021

BioMed Research International

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“…In this condition, heterozygous variants in COL10A1 lead to retention of abnormal type 10 collagen in the ER of chondrocytes. Excess type 10 collagen is thought to cause the bone deformity and short stature of MCDS, culminating in debilitating musculoskeletal pain (Dennis et al, 2021; Marzin & Cormier‐Daire, 2020). Carbamazepine (CBZ), a well‐established drug used to treat epilepsy, peripheral neuropathy, and bipolar disease, is being repurposed/repositioned for a clinical trial for MCDS.…”

Section: Precision Medicine In Skeletal Dysplasias Todaymentioning

confidence: 99%

Current state of the art in treatment of Mendelian disease: Skeletal dysplasias

Hoover‐Fong

2021

American J of Med Genetics Pt A

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The current state of the art in treatment of Mendelian disease, specifically skeletal dysplasias, benefits tremendously from Dr. Victor McKusick's early delineation and standardization of the nomenclature surrounding these conditions. Through close observation and careful description of each dysplasia to flesh out the nosologic backbone of the genetic skeletal disorders, individuals with the same diagnosis were identified and grouped together for genetic interrogation. These efforts have resulted in the identification of the genetic etiology of nearly all recognized skeletal disorders. This, in turn, is leading to disease‐specific treatment for many of the skeletal dysplasias in this new era of precision medicine. Furthermore, Dr. McKusick's natural history descriptions of many genetic skeletal disorders helped to establish the baseline disease state against which the effect of new treatment is compared.

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“…The severity of the disease apparently depends on the specific mutation and it was shown in cell culture models that different mutations may cause the disease by different molecular mechanisms ( 23 ). MED and PSACH are rare diseases and currently, there is no treatment available for human patients ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Structure, evolution and expression of zebrafish cartilage oligomeric matrix protein (COMP, TSP5). CRISPR-Cas mutants show a dominant phenotype in myosepta

et al. 2022

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COMP (Cartilage Oligomeric Matrix Protein), also named thrombospondin-5, is a member of the thrombospondin family of extracellular matrix proteins. It is of clinical relevance, as in humans mutations in COMP lead to chondrodysplasias. The gene encoding zebrafish Comp is located on chromosome 11 in synteny with its mammalian orthologs. Zebrafish Comp has a domain structure identical to that of tetrapod COMP and shares 74% sequence similarity with murine COMP. Zebrafish comp is expressed from 5 hours post fertilization (hpf) on, while the protein is first detectable in somites of 11 hpf embryos. During development and in adults comp is strongly expressed in myosepta, craniofacial tendon and ligaments, around ribs and vertebra, but not in its name-giving tissue cartilage. As in mammals, zebrafish Comp forms pentamers. It is easily extracted from 5 days post fertilization (dpf) whole zebrafish. The lack of Comp expression in zebrafish cartilage implies that its cartilage function evolved recently in tetrapods. The expression in tendon and myosepta may indicate a more fundamental function, as in evolutionary distant Drosophila muscle-specific adhesion to tendon cells requires thrombospondin. A sequence encoding a calcium binding motif within the first TSP type-3 repeat of zebrafish Comp was targeted by CRISPR-Cas. The heterozygous and homozygous mutant Comp zebrafish displayed a patchy irregular Comp staining in 3 dpf myosepta, indicating a dominant phenotype. Electron microscopy revealed that the endoplasmic reticulum of myosepta fibroblasts is not affected in homozygous fish. The disorganized extracellular matrix may indicate that this mutation rather interferes with extracellular matrix assembly, similar to what is seen in a subgroup of chondrodysplasia patients. The early expression and easy detection of mutant Comp in zebrafish points to the potential of using the zebrafish model for large scale screening of small molecules that can improve secretion or function of disease-associated COMP mutants.

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Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

Cited by 17 publications

References 106 publications

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

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

Current state of the art in treatment of Mendelian disease: Skeletal dysplasias

Structure, evolution and expression of zebrafish cartilage oligomeric matrix protein (COMP, TSP5). CRISPR-Cas mutants show a dominant phenotype in myosepta

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