SLC26A2 – Achondrogenesis Type IB

SLC26A2 (solute carrier family 26 member 2) encodes a sulfate–chloride antiporter critical for proteoglycan sulfation in cartilage. Biallelic loss‐of‐function variants in SLC26A2 cause autosomal recessive achondrogenesis type IB (MONDO:0010966), a prenatally lethal chondrodysplasia characterized by hydrops fetalis, severe micromelia, and undersulfated cartilage proteoglycans.

Multiple independent families harbor homozygous or compound heterozygous null alleles. A Japanese fetus was homozygous for a five–base deletion (c.1020_1022del (p.Val341del)) associated with achondrogenesis IB ([PMID:9637425]). Two unrelated Japanese pedigrees carry a recurrent missense variant c.1987G>A (p.Gly663Arg) ([PMID:31880411]). Additionally, eight further unrelated achondrogenesis IB probands, all lacking residual transporter activity, have been described ([PMID:8931695]). Together, at least 11 unrelated probands have confirmed biallelic severe alleles and autosomal recessive inheritance.

Segregation analysis in three pedigrees shows parents and siblings as asymptomatic heterozygous carriers, consistent with full recessivity; no additional affected relatives were reported.

Variant spectrum for achondrogenesis IB predominantly comprises frameshift and nonsense mutations yielding truncated proteins (e.g., p.Glu354Ter, p.Tyr589Ter) and critical in‐frame deletions (p.Val341del), as well as the recurring p.Gly663Arg alteration. No hypomorphic or deep‐intronic alleles have been implicated in this lethal phenotype.

Functional assays in patient fibroblasts demonstrate severely reduced sulfate uptake and proteoglycan undersulfation ([PMID:8571951]). Heterologous expression in HEK-293 cells confirms that ACG1B‐associated alleles abolish transporter function, whereas partial‐function alleles underlie milder chondrodysplasias ([PMID:15294877]). A knock-in mouse model carrying a hypomorphic SLC26A2 allele recapitulates key skeletal abnormalities, confirming pathogenic mechanism by loss of sulfate transport ([PMID:15703192]).

A common variant Thr689Ser was shown to occur in healthy controls (5/26 alleles) without functional impairment, identifying it as a polymorphism ([PMID:9637425]).

Integration of genetic and functional data supports SLC26A2 achondrogenesis IB as a strongly validated gene–disease relationship. The AR inheritance, null‐allele spectrum, consistent biochemical deficits, and animal model concordance underpin its clinical utility for diagnostic testing and prenatal counseling.

Key Take-home: Biallelic loss‐of‐function SLC26A2 variants cause lethal achondrogenesis IB via complete sulfate transport deficiency; robust genetic and functional evidence supports routine inclusion in prenatal skeletal dysplasia panels.

References

• American Journal of Medical Genetics • 1998 • Mutational analysis of the DTDST gene in a fetus with achondrogenesis type 1B. PMID:9637425
• American Journal of Medical Genetics Part A • 2020 • Two unrelated pedigrees with achondrogenesis type 1b carrying a Japan-specific pathogenic variant in SLC26A2. PMID:31880411
• Human Genetics • 1996 • Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. PMID:8931695
• 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 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

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