In the current study, we report a four-generation family of early-onset hip osteoarthritis caused by a heterozygous mutation of c.1153G > T. Their prominent symptoms include severe osteoarthritis, knees pain, and femoral head necrosis, same as COMP-associated MED. According to the ACMG and our study, this variation a) is absent from the records of any frequency database like 1000 Genomes Project and ExAC, indicates this mutation is a rare mutation (PM2); b) located in a well-established functional domain (PM1); c) co-segregated with disease in multiple affected family members (PP1); d) have computational evidence supporting a deleterious effect on the gene (PP3). Basing on the evidence above, we assessed this mutation as pathogenic, and played an important role in the genetic etiology of this family.
A different mutation at the same position (c.1153G > A, p. D385N) has been shown to cause MED [20]. In that reported sporadic case, the patients have mild short stature and early onset osteoarthrosis, diagnosed as the severe form of MED- “Fairbank type”. In another study, the authors reported a pedigree with severe hip osteoarthrosis. After WES, the c.1153G > A mutation of the COMP gene was identified as related to the MED phenotype of this family. The phenotype of pedigrees reported by Liu et al. is partially similar to our patient [21]. They are mainly manifested as necrosis of the femoral head, but there is no phenotype such as flatfoot. In the current study, the c.1153G > T mutation was predicted to lead to amino acid substitution from Asp to Tyr, which implies that other substitution of this position can also lead to the occurrence of classical phenotype of MED.
The precise function and pathogenic mechanism of mutant COMP in the MED have not been fully defined. However compelling evidence indicates that COMP play an important role in maintaining the integrity of cartilage and extracellular matrix. The misfolding of the mutant COMP affects its normal secretion from the endoplasmic reticulum of the affected chondrocytes, and this intracellular retention is toxic to chondrocytes, resulting in premature chondrocyte death [22]. These events which reduce the number of chondrocytes in the growth plate ultimately reduce linear growth with the phenotypic outcome being dwarfism. Moreover, the reduction of COMP secretion would affect the assembly of collagen fibers [23], leading to a decrease in articular cartilage mechanical strength and the occurrence of early-onset osteoarthritis [24–26]. At the meantime, the calcium binding T3 repeat of COMP has been shown to provide support for chondrocyte attachment [27]. The changes in the 3-D calcium-dependent structure of the mutant COMP may impress chondrocyte attachment and contribute to the development of MED phenotype. Briggs et al. [28] confirmed that both PSACH and MED mutations are predominantly located within the type III repeat domain of COMP (90% of mutation), meanwhile, they found that missense mutations and in-frame insertion/deletion of single residue in T35 − 7 usually cause PSACH, while missense mutations in T33 − 4 more often cause MED. Our mutation c.1153G > A is located in the T33 − 4 repeat of COMP. Therefore, the mechanisms mentioned above may explain some phenotypes of our family, such as mild short stature and early-onset osteoarthritis.
Club foot is a rare and peculiar radiological finding which has been observed mostly in association with recessive multiple epiphyseal dysplasia (rMED). In Makitie's study, they found that rMED patients with club foot carry homozygous/compound heterozygous mutations in SLC26A2 at birth [29]. Superti-Furga et al. [30] found the rMED patients with normal stature, club foot, and double layered patella caused by a DTDST mutation. Interestingly, in our study, we found that all affected individuals in our family have flatfoot expect single patient (Ⅲ-1). Meanwhile, other intra-familial differences of phenotype could be observed in our family. For example, one patient (Ⅲ-18) have mild sacroiliitis, low back pain at 18 years old, who also have gait abnormalities, mild short stature, flatfoot, and hip osteoarthritis. In addition, two male patients (Ⅱ-9, Ⅱ-13) have brachydactyly, but other patients do not have this phenotype. Furthermore, male patients in this family are generally shorter in height, but we are not sure if this is related to the mutation of c.1153G > T. In the pedigree study conducted by Sakamoto et al., they also observed the intra-familial differences in the severity of their four-generation family: the radiological manifestation of the knees were more severe in the proband’s father than in the proband, and the stature of young sister is shorter than of proband [31]. Otherwise, Liu et al. [21] also found similar characteristics of intra-familial differences, a twin brother of their family has more severe symptoms of walking limitation than other family member. These intra-familial differences of phenotype are difficult to explain by genetic factors but can be explained by the effects of environmental factors [1, 3].
In conclusion, we identified a novel heterozygous pathogenic mutation in COMP from an AD-MED family, exhibiting COMP-associated MED, and other phenotypes like flatfoot. Our results expanded the mutational and phenotypic spectrum of COMP and suggested that the mutation of the key amino acid residues would be disease-causing.