SLC36A2 – Iminoglycinuria

Iminoglycinuria (IG) is an autosomal recessive renal transport disorder characterized by impaired reabsorption of glycine and the imino acids proline and hydroxyproline, manifesting as aminoaciduria. A related condition, hyperglycinuria (HG), presents with isolated glycine clearance but lacks iminoaciduria. Although clinically recognized for decades, the molecular basis of IG and HG remained undefined until recent candidate gene analyses.

In a sequencing study of seven unrelated families identified through newborn IG screening programs (PMID:19033659), biallelic variants in SLC36A2 were implicated as the principal cause of IG. The inheritance pattern was semidominant: individuals homozygous or compound heterozygous for nonfunctional alleles exhibited IG, whereas heterozygous carriers manifested HG.

The variant spectrum included a canonical splice donor mutation, c.164+1G>A, and a representative missense substitution, c.260G>T (p.Gly87Val). The c.260G>T (p.Gly87Val) allele served as a paradigmatic pathogenic variant in this cohort, and no recurrent or founder mutations were detected. These two variant classes—splice and missense—define the core pathogenic mechanism in IG.

Segregation analysis confirmed clear cosegregation of nonfunctional SLC36A2 alleles with IG in affected relatives, while single-allele carriers displayed isolated glycinuria without iminoaciduria (PMID:19033659). This dosage-dependent effect underscores a classical autosomal recessive but semidominant inheritance model.

Functional expression assays in Xenopus oocytes demonstrated abolished proton-coupled transport activity for both the splice donor and missense variants, whereas other alleles with partial residual function correlated with intermediate biochemical phenotypes (PMID:19033659). These results establish loss of transporter function as the underlying disease mechanism.

Collectively, robust genetic and experimental data support a Strong ClinGen classification for the SLC36A2–Iminoglycinuria association. Genetic testing of SLC36A2 variants enables definitive diagnosis of IG, informs carrier screening, and guides differential diagnosis in renal aminoacidurias. Key Take-home: SLC36A2 loss-of-function variants underlie IG and exhibit clear dosage sensitivity with direct clinical utility.

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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