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

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.

Further evidence for allelic heterogeneity in Hartnup disorder.

Hartnup disorder is an autosomal recessive impairment of amino acid transport in kidney and intestine. Mutations in SLC6A19 have been shown to cosegregate with the disease in the predicted recessive manner; however, in two previous studies (Seow et al., Nat Genet 2004;36:1003-1007; Kleta et al.

A protein complex in the brush-border membrane explains a Hartnup disorder allele.

Protein absorption in the intestine is mediated by proteases and brush-border peptidases together with peptide and amino acid transporters. Neutral amino acids are generated by a variety of aminopeptidases and carboxypeptidases and are subsequently taken up by the amino acid transporter B(0)AT1 (SLC6A19), which is mutated in Hartnup disorder. Coexpression of B(0)AT1 together with the brush-border carboxypeptidase angiotensin-converting enzyme 2 (ACE2) in Xenopus laevis oocytes led to a dramatic increase of transporter expression at the oocyte surface.

The orphan transporter v7-3 (slc6a15) is a Na+-dependent neutral amino acid transporter (B0AT2).

Transporters of the SLC6 (solute carrier 6) family play an important role in the removal of neurotransmitters in brain tissue and in amino acid transport in epithelial cells. In the present study, we demonstrate that mouse v7-3 (slc6a15) encodes a transporter for neutral amino acids. The transporter is functionally and sequence related to B(0)AT1 (slc6a19) and was hence named B(0)AT2.

Characterization of mouse amino acid transporter B0AT1 (slc6a19).

The mechanism of the mouse (m)B0AT1 (slc6a19) transporter was studied in detail using two electrode voltage-clamp techniques and tracer studies in the Xenopus oocyte expression system. All neutral amino acids induced inward currents at physiological potentials, but large neutral non-aromatic amino acids were the preferred substrates of mB0AT1. Substrates were transported with K0.

Molecular cloning of the mouse IMINO system: an Na+- and Cl--dependent proline transporter.

Neurotransmitter transporters of the SLC6 family play an important role in the removal of neurotransmitters in brain tissue and in amino acid transport in epithelial cells. Here we demonstrate that the mouse homologue of slc6a20 has all properties of the long-sought IMINO system. The mouse has two homologues corresponding to the single human SLC6A20 gene: these have been named XT3 and XT3s1.

Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder.

Resorption of amino acids in kidney and intestine is mediated by transporters, which prefer groups of amino acids with similar physico-chemical properties. It is generally assumed that most neutral amino acids are transported across the apical membrane of epithelial cells by system B(0). Here we have characterized a novel member of the Na(+)-dependent neurotransmitter transporter family (B(0)AT1) isolated from mouse kidney, which shows all properties of system B(0).