HPRT1 – Gout

HPRT1 encodes hypoxanthine-guanine phosphoribosyltransferase, a key enzyme in purine salvage. Hemizygous loss-of-function in males and carrier status in females leads to overproduction of uric acid, manifesting as hyperuricemia and gout with an X-linked recessive inheritance pattern.

Genetic evidence arises from nine unrelated probands (PMID:10451080,15536609,15334740,15862284,26073243,27288985,9868957,1483694,17309125) presenting with gout or hyperuricemia caused by distinct HPRT1 mutations. Variants include missense substitutions (e.g., c.152G>A (p.Arg51Gln) and c.206A>T), frameshifts and splicing defects. One representative hypomorphic allele, c.481G>T (p.Ala161Ser), was identified in a patient with severe tophaceous gout refractory to allopurinol (PMID:27288985).

Segregation analysis in a Taiwanese aboriginal pedigree demonstrated the HPRT(Tsou) variant (c.152G>A (p.Arg51Gln)) co-segregating with hyperuricemia in ten affected male and female relatives across two generations (PMID:10451080).

The variant spectrum includes six missense mutations, four novel point mutations in exon 2 or exon 3, and at least two splice-site defects. Clinical severity correlates inversely with residual enzyme activity, with partial deficiencies causing gout and near-complete loss resulting in Lesch-Nyhan syndrome.

Functional assays in erythrocytes and lymphocytes show HPRT activity reduced to 5–30% of normal in gout patients, confirming haploinsufficiency as the pathogenic mechanism and correlating with increased serum urate levels (PMID:15536609,15334740,27288985).

A regulatory defect without coding region mutation has been reported (normal HPRT coding but reduced activity), highlighting non-coding mechanisms (PMID:15862284). Overall, the evidence supports a strong X-linked recessive association between HPRT1 and gout.

Key take-home: Screening for HPRT1 variants in male patients with early-onset or refractory gout can guide diagnosis, management, and genetic counseling.

References

• The Journal of Rheumatology • 1999 • Identification of a new single nucleotide substitution on the hypoxanthine-guanine phosphoribosyltransferase gene (HPRT(Tsou)) from a Taiwanese aboriginal family with severe gout. PMID:10451080
• Metabolism: Clinical and Experimental • 2004 • Identification of a new point mutation in hypoxanthine phosphoribosyl transferase responsible for hyperuricemia in a female patient. PMID:15536609
• Journal of Inherited Metabolic Disease • 2004 • Kelley-Seegmiller syndrome due to a new variant of the hypoxanthine-guanine phosphoribosyltransferase (I136T) encoding gene (HPRT Marseille). PMID:15334740
• Molecular Genetics and Metabolism • 2005 • Normal HPRT coding region in a male with gout due to HPRT deficiency. PMID:15862284
• Clinica Chimica Acta • 2016 • Genetic background of uric acid metabolism in a patient with severe chronic tophaceous gout. PMID:27288985

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