Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

Abstract

Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia. Mutations in six genes (COMP, COL9A1, COL9A2, COL9A3, MATN3 and DTDST) have been reported, but the genotype -phenotype correlations and the proportions of cases due to mutations in these genes are still not well characterized. We performed a clinical, radiological and molecular analysis of known MED genes on 29 consecutive MED patients. The mutation analysis resulted in identification of the DTDST mutation in four patients (14%), the COMP mutation in three (10%) and the MATN3 mutation in three (10%). Thus, a disease-causing mutation was identified in 10 patients altogether (34%). The phenotypic features observed in the patients with mutations were in accordance with previously described phenotypes, but two new distinct phenotypic entities were identified in patients in whom no mutation was found. One of them was characterized by severe, early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks. The other phenotype was characterized by 'mini-epiphyses', resulting in severe dysplasia of the proximal femoral heads. The findings suggest that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci by mutation analysis and finding of specific subgroups among these patients.

Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population

“…This detection rate is higher than those reported in comparable studies of Western populations [Briggs and Chapman, 2002;Jakkula et al, 2003;Jackson et al, 2004;Jakkula et al, 2005]. The increased rate may result from the analysis method used; in previous studies, most COMP and type IX collagen genes were screened using conformation sensitive gel electrophoresis, or only limited regions of each gene were examined.…”

“…This algorithm can improve the efficiency of genetic analysis for MED, but the unidentified gene(s) that account for as many as half of MED cases still present a challenge. The absence of known gene mutations despite our complete sequence analysis of these genes indicates the existence of additional MED gene(s), which is also supported by linkage analysis [Jakkula et al, 2005]. Identification of new MED gene(s) will help refine the strategy for genetic analysis of MED patients.…”

“…Jackson et al [2004] identified nine MATN3 mutations in 50 unrelated individuals from several Western countries who lack mutations in specific exons (mutation hot-spots) of the COMP and type IX collagen genes. Analysis of 29 consecutive European MED patients identified known gene mutations in only about one-third of cases [Jakkula et al, 2005]. In that study, however, only one exon in each of the type IX collagen genes was examined.…”

Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study

“…In an early study on Caucasian population reported the proportions of DTDST as 14%, COMP as 10%, MATN3 as 10%, and unknown as 66% in 29 MED patients [7]. Subsequent studies reported that COMP (47% and 50%) was the most common causative gene followed by DTDST (25% and 28%), while MATN3 (17%) and COL9A1, 2, and 3 (8%) comprised only a small portion of these MED patients [3,9].…”

Genetic analysis of skeletal dysplasia: recent advances and perspectives in the post-genome-sequence era

“…Of course, further identification of unknown MED genes is necessary for this system. Known gene mutations were found in fewer than half of the MED patients (Jackson et al 2004;Jakkula et al 2005). Familial cases not linked to known MED loci exist (Jakkula et al 2005; our unpublished experience).…”