SLC29A3 – H syndrome

SLC29A3 encodes the equilibrative nucleoside transporter hENT3, localized to lysosomes and mitochondria, and is essential for intracellular nucleoside salvage. Biallelic pathogenic variants in SLC29A3 underlie H syndrome, a multisystem autosomal recessive disorder marked by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, hypogonadism, hearing loss, short stature and flexion contractures ([PMID:20619369]).

H syndrome manifests by early childhood with symmetric indurated hyperpigmented and hypertrichotic skin lesions, systemic histiocytosis, insulin-dependent diabetes, and endocrinopathies. Over 79 patients from diverse ethnicities have been described, illustrating marked interfamilial and intrafamilial variability ([PMID:24172204]).

Inheritance is autosomal recessive, typically in consanguineous pedigrees. Segregation analyses in a single large family demonstrated three affected individuals compound heterozygous or homozygous for SLC29A3 variants, confirming co-segregation with disease ([PMID:20619369]).

The variant spectrum includes missense, frameshift, splice-site and nonsense changes. A recurrent founder variant, c.1279G>A (p.Gly427Ser), and other LoF alleles (e.g., c.1309G>A (p.Gly437Arg)) account for multiple cases across populations, supporting allelic heterogeneity and founder effects ([PMID:20619369]).

Functional studies reveal that H syndrome–associated mutations severely reduce nucleoside transport activity of hENT3, impair protein stability and mislocalize the transporter, leading to lysosomal dysfunction ([PMID:20595384]).

No studies have refuted the association; all reported SLC29A3 variants are consistent with loss of function. The definitive gene–disease relationship enables accurate molecular diagnosis and informs carrier screening, prognostication, and emerging targeted therapies.

Key Take-home: Biallelic SLC29A3 mutations cause a definitive autosomal recessive H syndrome with characteristic dermatologic and multisystem involvement; genetic testing and hENT3 functional assays are clinically informative.

References

• European Journal of Medical Genetics • 2010 • Expanding the clinical spectrum of SLC29A3 gene defects. PMID:20619369
• Journal of the American Academy of Dermatology • 2014 • H syndrome: the first 79 patients. PMID:24172204
• PLoS Genetics • 2010 • Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PMID:20140240
• The Journal of Biological Chemistry • 2010 • Human equilibrative nucleoside transporter-3 (hENT3) spectrum disorder mutations impair nucleoside transport, protein localization, and stability. PMID:20595384

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