SLC6A20 – Hyperglycinuria

Hyperglycinuria is characterized by elevated urinary glycine excretion without iminoaciduria, reflecting impaired renal glycine reabsorption. Pathogenic heterozygous variants in SLC6A20 have been implicated as a semidominant cause of hyperglycinuria in both cohort and family studies ([PMID:19033659]).

In a candidate gene sequencing study of seven families identified through newborn screening, a classical semidominant inheritance pattern was demonstrated: two nonfunctional alleles in SLC36A2 produced iminoglycinuria, whereas a single nonfunctional SLC36A2 allele or heterozygous SLC6A20 variants conferred isolated hyperglycinuria. Functional assays of SLC6A20 c.596C>T (p.Thr199Met) showed significantly reduced glycine transport activity, consistent with clinical hyperglycinuria ([PMID:19033659]).

A recent case report described a Chinese family in which the proband and her mother exhibited hyperglycinuria and both carried a heterozygous SLC6A20 c.1072T>C (p.Cys358Arg) variant; segregation was observed in one additional affected relative, reinforcing the semidominant effect of single SLC6A20 alleles ([PMID:36820062]).

To date, two missense SLC6A20 variants have been reported in hyperglycinuria: c.596C>T (p.Thr199Met) and c.1072T>C (p.Cys358Arg). Familial segregation includes at least one additional affected relative. Functional transport assays concordantly demonstrate impaired SLC6A20-mediated glycine uptake.

Mechanistically, these missense variants reduce SLC6A20 transporter function, leading to decreased renal glycine reabsorption and elevated urinary glycine. No studies to date dispute this gene–disease association.

Key take-home: Heterozygous SLC6A20 variants are moderately supported as a semidominant cause of hyperglycinuria; genetic testing for SLC6A20 should be considered in patients with unexplained hyperglycinuria to guide diagnosis and counseling.

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
• Open medicine (Warsaw, Poland) • 2023 • Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report. PMID:36820062

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