Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W

Abstract

M ultiple epiphyseal dysplasia (MED) is a generalised skeletal dysplasia that although relatively mild is associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. In the past, the disorder was subdivided into the milder Ribbing type, usually with flattened epiphyses, 1 and the more severe Fairbank type with round epiphyses, 2 but many cases were not classifiable as clearly either type.3 MED can be caused by mutations in at least six separate genes: COMP, 4-7 collagen IX (COL9A1, COL9A2, and COL9A3), [8][9][10][11][12][13] matrilin 3 (MATN3), 15 and the sulphate transporter, DTDST (DTDST/SLC26A2). We have previously reported an adult with a recessively inherited form of MED (rMED) characterised by club feet, double layered patellae, and normal stature, who was homozygous for the mutation 862c>t/ R279W in the DTDST gene, previously associated with the achondrogenesis 1B-atelosteogenesis 2-diastrophic dysplasia spectrum. We now report on a group of 18 subjects who are homozygous for this point mutation, allowing a comprehensive assessment of this particular MED phenotype. Distinction of rMED is important because of its recessive inheritance (unlike other MED types) and genetic counselling implications. The frequency of the R279W mutation and the number of subjects with molecularly proven rMED identified since its description suggest that rMED may be more common than hitherto assumed. MATERIAL AND METHODSBlood or genomic DNA was sent to the Zurich centre for DTDST mutation analysis because of clinical and radiographic signs similar to the reported case of rMED, 20 or because of a clinical diagnosis of MED and negative mutation analysis of COMP or collagen IX genes. Genomic DNA was extracted from blood leucocytes using standard protocols and was subjected to DTDST mutation analysis. The fragment of interest, that is, the 5′ part of exon 3, was amplified according to the procedure previously described.18 20 The PCR fragment was digested with the restriction endonuclease StyI. Results were visualised on agarose gels in the presence of positive and negative controls. As the nucleotide change 862c>t (leading to amino acid substitution R279W) creates a new restriction site for StyI, heterozygous and homozygous patients can be distinguished from wild type homozygous subjects. In all subjects with a positive StyI digestion, the genotype was confirmed by direct sequencing of the fragment amplified in a second PCR. The ABI Prism Big Dye Terminator Ready Reaction Kit and protocol were used for sequencing in an ABI Prism 310 Genetic Analyzer. In all subjects who were not homozygous for R279W, a complete DTDST mutation screening was performed 19 to test for the presence of other mutations.When R279W homozygosity was identified, the referring physician was asked to participate in this study by sending photographs and radiographs, as well as by completing a questionnaire about family and personal history, symptoms leading to diagnosis, clinical c...

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

“…The p.R279W is a common SLC26A2 mutation. Compound heterozygotes or homozygotes of this mutation usually manifest severe skeletal dysplasia, although patients with milder phenotypes have been reported 31 .…”

Solute Carrier Family 26 Member a2 (Slc26a2) Protein Functions as an Electroneutral SO42−/OH−/Cl− Exchanger Regulated by Extracellular Cl−

“…The central role of Slc26a2 in supplying the bulk of cellular SO 4 2Ϫ is evident from the lethality of deletion of the SLC26A2 gene in humans and mice (20,22), mainly due to under-sulfation of proteoglycans leading to aberrant development (23). Indeed, measurement of SO 4 2Ϫ uptake in fibroblast from patients with a severe form of the disease showed reduced or lack of SO 4 2Ϫ uptake (20,24).…”

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

“…Detailed clinical and mutation data have been reported previously for four of these patients. Three of these patients with clinical findings consistent with rMED had homozygous DTDST mutations; 14,15 one had radiographic findings typical of EDM1 and was found to have a COMP mutation. 18 Of the remaining 26 patients, 25 consented to participate in the study.…”

“…Taking together with the previously reported mutations, 10,14,15,18,19 Figure 5 Patient 16 was diagnosed with MED in early childhood. At 10 years he was asymptomatic but had genua vara, increased lumbar lordosis, short stature (o3%) and generalized joint laxity.…”