Recurrent c.G1636A (p.G546S) mutation of COL2A1 in a Chinese family with skeletal dysplasia and different metaphyseal changes: a case report

Abstract

BackgroundMutations in the COL2A1 gene cause type II collagenopathies characterized by skeletal dysplasia with a wide spectrum of phenotypic severity. Most COL2A1 mutations located in the triple-helical region, and the glycine to bulky amino acid substitutions (e.g., glycine to serine) in the Gly-X-Y repeat were identified frequently. However, the same COL2A1 mutations are associated with different phenotypes and the genotype-phenotype relationship is still poorly understood. Therefore, the studies of more patients about the recurrent mutations in COL2A1 will be needed for further research to provide more comprehensive clinical and genetic data. In this paper, we report a rare recurrent c.G1636A (p.G546S) mutation in COL2A1 associated with different metaphyseal changes in a Chinese family.Case presentationThe proband (III-3) was the second child of the family with skeletal dysplasia. She was 2 years and 3 months old with disproportional short stature, short neck, pectus carinatum, genu varum, bilateral pes planus, and obvious waddling gait. Notably, she displayed severe metaphyseal lesions, especially typical “dappling” and “corner fracture” appearance, whereas no particular metaphyseal involvement was detected in the proband’s mother (II-3) and elder sister (III-2) in the family. We identified a heterozygous mutation (c.1636G > A) in COL2A1 in the three patients, causing the substitution of glycine to serine in codon 546. Although the same mutation has been reported in two previous studies, the phenotypes of the previous patients were different from those of our patients, and the characteristic “dappling” and “corner fracture” metaphyseal abnormalities were not reported previously.ConclusionsIn this study, we identified a c.G1636A (p.G546S) mutation in the COL2A1 associated with different metaphyseal changes, which was never reported in the literature. Our findings revealed a different causative amino acid substitution (glycine to serine) associated with the “dappling” and “corner fracture” metaphyseal abnormalities, and may provide a useful reference for evaluating the phenotypic spectrum and variability of type II collagenopathies.

Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I

“…In addition, there was a polymorphism of clinical manifestations in two probands with a similar variant, where a substitution of glycine to serine at the 546 nucleotide position was detected. One of the patients had typical signs of SEMD and another one had a mild phenotype of SED with normal growth, as confirmed by the data of Chen J. et al [ 27 ], where an interfamily clinical polymorphism was identified in patients with this pathogenic variant. In two patients with newly identified substitutions leading to glycine substitution: c.1348G>C (p.Gly450Arg) and c.3554G>A (p.Gly1185Glu), radiography revealed the presence of enchondroma-like changes in metaphyses, anisospondylia, limb length discrepancy, and abnormal ossification pattern of the pubic bones which are typical for dyspondyloenchondromatosis ( Figure 4 ).…”

“…To date, no clear genotype–phenotype correlations have been obtained in type II collagenopathies, which is most likely associated with the existence of the inter- and intrafamilial variability of clinical manifestations, differences in the specificity of clinical manifestations in patients with the same pathogenic variants, age-related evolution of phenotypes, and evidence of marked genetic heterogeneity due to some cases with an autosomal recessive type of inheritance [ 13 , 15 , 23 , 24 , 25 , 26 ]. Nevertheless, conducting a clinical and genetic analysis of various nosological variants of the skeletal collagenopathies spectrum can improve our understanding of the pathogenetic mechanisms and more accurately predict their course at the early stages, improving an individual’s medical care and quality of life [ 27 ].…”

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

“…[31][32][33] It has been postulated that mutations in the triplehelical domain of procollagen a chains can delay the folding of the protein into the triple-helical conformation, thus leading to posttranslational over modification of the protein. [34,24,35] In this study, all affected individuals were found to carry p.Gly1170Ser mutation in exon 50 of COL2A1 gene, which resulted in a change from glycine to serine at codon 1170 (Gly1170Ser). A Gly1170Ser mutation potentially interrupts the mandatory Gly-X-Y triplet sequence required for the normal formation of stable triple-helical type II collagen molecules, which could further lead to the degradation of premature collagen molecules, or to the production of overmodified type II collagen.…”

A novel mutation of COL2A1 in a large Chinese family with avascular necrosis of the femoral head

“…The exception is glycine to serine substitutions. Glycine to serine substitutions, unlike glycine to nonserine residue substitutions, produced variable phenotypes, with both inter- and intra-familial phenotypic variation [ 21 , 22 ]. In type I collagenopathies, the severity of the disease has been correlated with the size and charge of the substituted amino acid, specifically Ala < Ser < Cys < Arg < Glu < Asp < Val, in order from least to most disruptive [ 23 ].…”