SLC26A2 – Diastrophic Dysplasia

Diastrophic dysplasia (DTD; MONDO:0009107) is an autosomal recessive chondrodysplasia characterized by limb shortening, joint contractures, and spinal deformities. Affected infants present at birth with rhizomelia, mesomelia, hitch-hiker thumb, and cleft palate. Radiographic hallmarks include severe platyspondyly, metaphyseal widening, and fibular overgrowth. The condition has an incidence of approximately 1 in 100,000 live births and follows a continuous phenotypic spectrum with atelosteogenesis type II and achondrogenesis type IB at the severe end of the spectrum (PMID:8571951).

The SLC26A2 gene encodes a sulfate/chloride antiporter (DTDST) essential for proteoglycan sulfation in growth plate chondrocytes. Biallelic loss-of-function or hypomorphic missense variants in SLC26A2 disrupt sulfate uptake, leading to undersulfated cartilage matrix and impaired endochondral ossification. Diastrophic dysplasia is inherited in an autosomal recessive manner, with parents of affected individuals typically heterozygous carriers of pathogenic alleles.

Genetic evidence includes over 30 distinct SLC26A2 mutations identified in more than 30 probands across consanguineous and non-consanguineous families (PMID:11241838). Segregation analyses in multiple pedigrees confirm biallelic inheritance, with parents and unaffected siblings each harboring single heterozygous variants. A recurrent founder missense allele, c.835C>T (p.Arg279Trp), is observed in diverse populations and underlies both DTD and recessive multiple epiphyseal dysplasia when in homozygosity or compound heterozygosity (PMID:8931695).

Case reports document homozygous and compound heterozygous SLC26A2 genotypes in classical DTD. The c.1361A>C (p.Gln454Pro) change was identified in a child with platyspondyly, metaphyseal widening, and fibular overgrowth (PMID:10466420). The Finnish founder splice variant c.-26+2T>C and p.Arg279Trp combination yields a DTD phenotype in several families, whereas more severe alleles such as c.532C>T (p.Arg178Ter) compound with p.Arg279Trp produce intermediate atelosteogenesis type II–DTD presentations (PMID:15316973).

Functional assays demonstrate that null mutations abolish sulfate transport, whereas partial-function alleles retain 17–62% activity of wild-type DTDST. In Xenopus oocytes and HEK‐293 cells, variants such as p.Arg279Trp and p.Gln454Pro display residual transport, correlating with milder phenotypes, while null alleles like p.Arg178Ter and p.Val341del yield defective uptake (PMID:11448940). Recent cryo-EM structures of human SLC26A2 elucidate substrate-binding dynamics and provide structural context for pathogenic mutations (PMID:38684689).

A knock-in mouse model harboring a hypomorphic SLC26A2 allele recapitulates key features of human DTD, including cartilage proteoglycan undersulfation, irregular chondrocyte size, delayed ossification, and joint contractures; this animal model supports haploinsufficiency as the primary mechanism of disease (PMID:15703192).

Integration of genetic, biochemical, and animal data fulfills ClinGen criteria for a definitive gene–disease relationship. Molecular diagnosis via targeted sequencing of SLC26A2 informs recurrence risk, enables prenatal or preimplantation genetic testing, and guides management of skeletal dysplasia. Key take-home: Biallelic SLC26A2 variants cause autosomal recessive diastrophic dysplasia through impaired sulfate transport of cartilage proteoglycans, and genetic confirmation is critical for accurate diagnosis and counseling.

References

• American journal of human genetics • 1996 • Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias PMID:8571951
• Clinical genetics • 1999 • Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia PMID:10466420
• 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
• Human mutation • 2001 • Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance PMID:11241838
• 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 • 2005 • A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype PMID:15703192
• Nature communications • 2024 • Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2 PMID:38684689

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