SLC26A2 – Multiple Epiphyseal Dysplasia Type 4

Autosomal recessive multiple epiphyseal dysplasia type 4 (MED-4; MONDO:0009189) is caused by biallelic pathogenic variants in the sulfate transporter gene SLC26A2 (HGNC:10994). MED-4 manifests in childhood with disproportionate short stature, early-onset osteoarthritis, double-layered patellae and hip dysplasia, reflecting epiphyseal cartilage undersulfation.

Genetic evidence for SLC26A2 in MED-4 includes over 64 unrelated probands across multiple cohorts: 55 Russian patients (c.835C>T and c.1957T>A alleles) (PMID:36140680), seven Swedish patients with Finnish founder IVS1+2T>C and R279W alleles (PMID:24598000), and four Portuguese patients (Arg279Trp compound genotypes) (PMID:21155763). Homozygous or compound heterozygous missense, splice-site, and loss-of-function variants segregate with disease in multiple families under an autosomal recessive mode of inheritance.

The variant spectrum in MED-4 is dominated by the recurrent missense allele c.835C>T (p.Arg279Trp), which when homozygous causes the mild rMED phenotype and when compounded yields classical MED-4 or diastrophic dysplasia (PMID:12966518). Other common alleles include the Finnish founder splice variant c.-26+2T>C and the hypomorphic missense c.1957T>A (p.Cys653Ser). Splice-site, nonsense, and frameshift mutations further modulate phenotypic severity.

Segregation analyses demonstrate multiple affected sibling pairs and compound heterozygotes with parents confirmed as carriers, supporting pathogenicity of biallelic alleles. One Swedish pedigree provided segregation of rMED in two siblings (PMID:24598000). Overall, at least one additional affected relative has been documented.

Functional assays in patient-derived fibroblasts and heterologous HEK-293 cells show residual sulfate transport activity correlating with clinical severity: R279W retains ~40–60% function, whereas null alleles abolish transport (PMID:15294877). A Dtdst hypomorphic mouse model reproduces growth retardation, epiphyseal dysplasia and cartilage undersulfation (PMID:15703192). High-resolution cryo-EM structures of human SLC26A2 reveal substrate-binding dynamics and explain loss-of-function of pathogenic alleles (PMID:38684689).

Together, genetic and experimental evidence conclusively establish SLC26A2 as the MED-4 gene. Loss of sulfate/chloride antiporter activity in chondrocytes underlies epiphyseal cartilage undersulfation and clinical features. Extensive case series, segregation, functional concordance, animal models, and structural data fulfill ClinGen criteria for a Definitive gene–disease relationship.

Key take-home: Biallelic SLC26A2 variants cause autosomal recessive MED-4 with early-onset epiphyseal dysplasia and joint deformities; genetic testing and functional assays inform diagnosis, counseling, and potential therapeutic targeting.

References

• 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
• American journal of medical genetics. Part A • 2003 • Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign PMID:12966518
• Clinical genetics • 2015 • SLC26A2 disease spectrum in Sweden - high frequency of recessive multiple epiphyseal dysplasia (rMED) PMID:24598000
• Clinical genetics • 2011 • Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population PMID:21155763
• Genes • 2022 • Clinical and Genetic Characteristics of Multiple Epiphyseal Dysplasia Type 4 PMID:36140680
• Nature communications • 2024 • Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2 PMID:38684689

Evidence Based Scoring (AI generated)