Chapter 194

## Abstract

Abstract

1. Familial iminoglycinuria is a benign inborn error of membrane transport. It mainly involves a membrane carrier in the renal tubule with a preference for L-proline, hydroxy-L-proline, and glycine, resulting in net reabsorption. The iminoglycinuria phenotype is autosomal recessive.

2. Homozygotes retain appreciable tubular reabsorption of the imino acids and glycine. The residual transport function is saturated at endogenous concentrations of substrate, and the normal competitive interactions between the imino acids and glycine during tubular reabsorption are absent. These seemingly paradoxical observations can be explained by multiple carriers participating in the reabsorption of imino acids and glycine. Loss of a carrier shared by the imino acids and glycine, and retention of other carriers with preferences for glycine and imino acids individually, can explain the homozygous iminoglycinuric phenotype.

3. A variant phenotype in which imino acid reabsorption has a normal maximal rate of reabsorption and the defect affects glycine reclamation more than proline probably indicates a Km variant.

4. Impaired intestinal transport of L-proline has been demonstrated in some, but not all, homozygotes. A transport defect has not been shown in the leukocytes or skin fibroblasts.

5. Obligate heterozygotes may be “hyperglycinuric” (incompletely recessive) or “silent” (completely recessive) for expression of the mutant allele. Phenotypic heterogeneity among probands and obligate heterozygotes indicates genetic heterogeneity.The different mutations appear to be allelic. Probands inheriting two “silent” mutant alleles, two “hyperglycinuric” alleles, or two different alleles have the same renal phenotype.

6. Several renal amino acid transport proteins and their corresponding cDNA clones have been isolated and classified into gene families. The common membrane carrier for imino acids and glycine has been identified as the proton-amino acid transporter SLC38A2 (PAT2). The specific carrier for proline and hydroxyproline has been identified as the Na+/Cl dependent IMINO transporter SLC6A20 (SIT1). SLC6A18 (B0AT3) has been identified as a glycine-preferring transporter in the mouse.

7. In humans with iminoglycinuria, mutations have been identified in the genes encoding SLC38A2, SLC6A20 and SLC6A18. Some of these, particularly in SLC6A18 occur at high frequency and may be considered SNPs. Mutations in SLC36A2 and SLC6A20, by contrast, are less frequent and functionally inactivate the transporter. The major gene affected in iminoglycinuria is SLC36A2. Genetic complexity is observed in some pedigrees, where iminoglycinuria is only observed in the presence of mutations in both SLC36A2 and in SLC6A20. The differential diagnosis of familial iminoglycinuria includes hyperprolinemia, in which iminoglycinuria occurs by a combined saturation-inhibition mechanism; the Fanconi syndrome, in which iminoglycinuria occurs as part of a generalized disturbance of transport; and the newborn, in whom hyperiminoglycinuria occurs in the first 6 months of life. Neonatal iminoglycinuria involves ontogeny of proline and glycine transport systems.

8. Several different forms of renal hyperglycinuria are appreciated that must be distinguished from the hyperglycinuric phenotype of the “incompletely recessive” heterozygote with renal iminoglycinuria.

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