SLC26A2 – Atelosteogenesis Type II

Atelosteogenesis Type II is a neonatally lethal autosomal recessive chondrodysplasia characterized by severe limb shortening and joint contractures. Biallelic variants in the solute carrier family 26 (sulfate transporter), member 2 gene (SLC26A2) cause defective sulfate transport in chondrocytes, leading to undersulfated cartilage proteoglycans and impaired endochondral ossification (PMID:8571951).

Inheritance follows an autosomal recessive pattern, with over 15 unrelated probands from at least seven families reported. Compound heterozygous and homozygous loss-of-function and hypomorphic variants segregate with disease in sibships and multiplex pedigrees (PMID:8571951; PMID:8931695).

The spectrum of pathogenic alleles includes nonsense, frameshift, and missense variants. Notably, the recurrent LoF allele c.532C>T (p.Arg178Ter) abolishes sulfate transport activity in functional assays (PMID:11448940).

In vitro studies in Xenopus oocytes and HEK293 cells demonstrate that AO-II–associated alleles have minimal residual sulfate uptake, correlating with phenotype severity (PMID:15294877). A knock-in mouse model harboring a hypomorphic Slc26a2 allele recapitulates growth retardation, chondrodysplasia, and proteoglycan undersulfation, confirming a loss-of-function mechanism (PMID:15703192).

No studies to date have reported alternative genes or modifiers that fully account for the AO-II phenotype in the absence of SLC26A2 variants.

Collectively, genetic, functional, and in vivo data support a definitive gene–disease relationship for Atelosteogenesis Type II. Key Take-home: Identification of SLC26A2 variants enables accurate diagnosis and informed reproductive counseling for families at risk of atelosteogenesis type II.

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
• Human Genetics • 1996 • Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. PMID:8931695
• 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
• Novartis Foundation Symposium • 2006 • Insights from a transgenic mouse model on the role of SLC26A2 in health and disease. PMID:17120769

Evidence Based Scoring (AI generated)