SLC36A2 – Hyperglycinuria

Hyperglycinuria is a rare renal tubular disorder characterized by isolated glycine excretion (HP:0003236) without accompanying iminoaciduria, leading to elevated urinary glycine and potential neurotoxic risk. Clinically, it is distinguished from iminoglycinuria by absence of proline and hydroxyproline wasting. Diagnosis relies on biochemical assays of aminoaciduria and confirmation by molecular testing of candidate transporters. Early recognition is important for monitoring and potential dietary management. Genetic counseling benefits from understanding the unique inheritance pattern of this condition.

Genetic etiology implicates SLC36A2, encoding the proton‐coupled amino acid transporter PAT2, identified via candidate sequencing in hyperglycinuria pedigrees. Analysis demonstrated a classical semidominant inheritance: heterozygous loss‐of‐function alleles confer hyperglycinuria, whereas biallelic null variants result in the more severe iminoglycinuria phenotype. This pattern underscores dosage sensitivity of SLC36A2 in renal glycine handling.

In 7 ([PMID:19033659]) unrelated families ascertained through newborn screening for iminoglycinuria, heterozygous splice donor c.164+1G>A and missense c.260G>T (p.Gly87Val) SLC36A2 variants were observed in individuals with isolated hyperglycinuria ([PMID:19033659]). No pathogenic alleles in SLC6A18, SLC6A19 or SLC6A20 were identified in these probands, supporting a primary role for SLC36A2 in hyperglycinuria.

The variant spectrum in hyperglycinuria includes both canonical splice‐site and missense mutations. The c.164+1G>A change predicts aberrant splicing and truncation, whereas the p.Gly87Val substitution abolishes transporter function. All reported alleles are absent from population databases, consistent with disease rarity and high penetrance in heterozygous carriers.

Functional assays in Xenopus oocytes confirmed complete loss of glycine transport for both c.164+1G>A and p.Gly87Val variants, correlating with reduced renal reuptake in vivo ([PMID:19033659]). Partial residual activity of other missense alleles was noted when in compound heterozygosity, explaining the more complex iminoglycinuria phenotype in biallelic individuals.

Taken together, heterozygous loss‐of‐function SLC36A2 variants underlie hyperglycinuria in a semidominant fashion. This association is supported by segregation data from seven families and concordant functional impairment in transport assays. Genetic testing of SLC36A2 can guide diagnosis, carrier testing, and counseling in individuals presenting with isolated hyperglycinuria.

References

• The Journal of clinical investigation • 2008 • Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. PMID:19033659

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