SLC26A2 – Multiple Epiphyseal Dysplasia

Recessive multiple epiphyseal dysplasia (rMED; MONDO:0016648) is caused by biallelic pathogenic variants in SLC26A2 (HGNC:10994), which encodes a sulfate/chloride antiporter essential for proteoglycan sulfation in cartilage. Patients present with epiphyseal dysplasia, joint pain, gait disturbance, brachydactyly, short stature, hip dysplasia, and scoliosis, often with multilayered or double-layered patellae. Diagnosis relies on radiographic evaluation and molecular confirmation of SLC26A2 variants.

Genetic evidence supports autosomal recessive inheritance with at least 13 unrelated probands across seven families harboring homozygous or compound heterozygous missense and loss-of-function alleles. Notably, c.835C>T (p.Arg279Trp) is recurrent in non-Finnish rMED patients ([PMID:10465113]). Other pathogenic alleles include c.797C>T (p.Thr266Ile), c.1957T>A (p.Cys653Ser), c.1153G>A (p.Asp385Asn), and frameshift variants leading to premature truncation. A screen of 29 MED patients identified DTDST mutations in four cases (14%) ([PMID:15523498]).

Segregation analyses demonstrate that affected individuals are homozygous or compound heterozygous for SLC26A2 variants, with parents and unaffected siblings as heterozygous carriers, confirming recessive transmission. In a Chinese family, two affected sibs inherited novel compound heterozygous variants, illustrating intrafamilial segregation ([PMID:29724173]).

Functional assays in Xenopus oocytes and HEK-293 cells show a spectrum of residual sulfate transport activity correlating with clinical severity: null or severely reduced transport for achondrogenesis 1B and atelosteogenesis, intermediate residual function for diastrophic dysplasia, and partial activity for rMED ([PMID:11448940], [PMID:15294877]). Transgenic SLC26A2-mutant mice recapitulate cartilage proteoglycan undersulfation, growth plate abnormalities, and skeletal dysplasia, providing an in vivo model for pathogenesis and therapy ([PMID:15703192]).

The collective genetic and experimental evidence supports a strong gene–disease association. No compelling conflicting data have been reported, although some MED cohorts (e.g., Japanese patients) show low DTDST mutation frequency, underscoring locus heterogeneity ([PMID:16691584]).

Key Take-home: Autosomal recessive SLC26A2 variants cause rMED through deficient sulfate transport, with molecular testing enabling definitive diagnosis, genetic counseling, and potential exploration of targeted therapies.

References

• Journal of medical genetics • 1999 • Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. PMID:10465113
• European journal of human genetics : EJHG • 2005 • Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. PMID:15523498
• Human molecular genetics • 2001 • Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. PMID:11448940
• Human molecular genetics • 2004 • Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. PMID:15294877
• Human molecular genetics • 2005 • A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype. PMID:15703192
• BMC medical genetics • 2018 • Dual novel mutations in SLC26A2 in two siblings with multiple epiphyseal dysplasia 4 from a Chinese family: a case report. PMID:29724173
• Human genetics • 1996 • Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. PMID:8931695

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