Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

Abstract

Iminoglycinuria (IG)is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B 0 AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes.

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

“…Thus, in contrast to humans, where the bulk of glycine uptake is mediated by PAT2 and B 0 AT1 (6), in mice it is likely to be mediated by B 0 AT1 and B 0 AT3. Consistent with this observation, we found in a previous study that humans lacking SLC6A18 do not show glycinuria (6). In addition to the insights gained into neutral amino acid uptake in kidney and intestine, this study represents the first demonstration that a lack of neutral amino acid uptake can cause significant changes in intracellular signaling processes and whole body homeostasis.…”

“…Recent studies from our laboratories provided evidence for the involvement of the proton-dependent glycine and proline transporter PAT2 (SLC36A2), the IMINO transporter (SLC6A20), and the glycine/alanine transporter B 0 AT3 (SLC6A18) in renal tubular transport of these two amino acids (6,19). Glycine transport in both wild type and Slc6a19 nullizygous mice was completely inhibited by leucine, pointing to another neutral amino acid transporter and at the same time excluding a significant role of PAT2.…”

“…Glycine and proline are poor substrates of B 0 AT1. As a result additional transporters are involved in the uptake of imino acids and glycine, such as PAT1 (SLC36A1), PAT2 (SLC36A2), and IMINO (SLC6A20) (6). Additional transport systems for other neutral amino acids in the kidney and intestine have been proposed; these include a specific intestinal transporter for methionine and phenylalanine (7) and the amino acid antiporter ASCT2 (SLC1A5) as a mediator of small neutral amino acids and glutamine uptake in kidney and intestine (8).…”

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria

“…In contrast, the majority of renal cysteine transport occurs in the oxidized state as cystine, facilitated by a heterodimeric exchanger, comprising SLC3A1 and SLC7A9, and thus can still occur when SLC1A1 is inactivated. As is the case for renal autosomal recessive disorders, such as Hartnup disorder (16,17) and iminoglycinuria (18), one functional allele suffices to prevent urinary wastage of amino acids. Our findings on SLC1A1 disruption in humans were in agreement with the DA phenotype reported in Slc1a1 nullizygous mice (6).…”

“…16 and 17); and iminoglycinuria (OMIM #242600; SLC36A2 and SLC6A20, ref. 18). DA has until now remained without a molecular explanation.…”