Beta-Aminoisobutyric Aciduria

A number sign (#) is used with this entry because of evidence that beta-aminoisobutyric aciduria (BAIBA) is caused by variation in the AGXT2 gene (612471) on chromosome 5p13.

Description

Beta-aminoisobutyric acid (BAIB) is a product of pyrimidine catabolism. Excretion of BAIB in urine is a benign 'metabolic polymorphism' present in many human populations (Scriver and Perry, 1989).

Clinical Features

Using paper chromatography, Crumpler et al. (1951) demonstrated urinary excretion of beta-aminoisobutyric acid (BAIB) in about 5% of healthy whites living in London, England. Harris (1953) showed that the phenotype is autosomal recessive. BAIB is a nonprotein amino acid, i.e., it is not a constituent amino acid of any protein.

Inheritance

From an extensive study in Japan, Yanai et al. (1969) concluded that high excretion is recessive. Heterozygotes excreted more BAIB than did homozygous low excretors. BAIB is an end product of pyrimidine metabolism; high excretion is frequent in Pacific populations that also show a high frequency of hyperuricemia.

Population Genetics

Simpson and Morton (1981) analyzed the data of Yanai et al. (1969) from a Japanese population. They concluded that 'high excretion of BAIB is determined by an incompletely recessive gene jointly with other familial factors.' The gene frequency was estimated to be 0.6. High excretion is much less frequent in Europeans. This is probably the most common mendelian metabolic variant in man.

Scriver and Perry (1989) stated that frequencies of the high excretor phenotype are up to 10% in whites, 15 to 30% in blacks, over 40% in Orientals, and approaching 95% in Southeast Asians. Asian Indians have a very low frequency.

Biochemical Features

Scriver and Perry (1989) reviewed the normal and disordered metabolism of BAIB. BAIB has a stable chiral structure at the alpha carbon. The R enantiomer (old name D-(minus)-BAIB) derives from thymine, the S enantiomer (L-plus-BAIB) from L-valine. Human urine contains R-BAIB almost exclusively (and it is this form that is excreted in excess in the hyper-BAIB trait), whereas the plasma pool is about 80% S-BAIB. The 'defect' is an impairment of R-BAIB catabolism due to deficient activity of a pyruvate-requiring transaminase, D-beta-aminoisobutyrate:pyruvate aminotransferase (EC 2.6.1.40) (Kakimoto et al., 1969; Taniguchi et al., 1972). This enzyme deficiency is compatible with in vivo observations that high excretors have impaired ability to degrade R-BAIB and thymine; that R-BAIB loading increases R-BAIB excretion of high excretors and nonexcretors; and that valine loading does not increase BAIB excretion in high excretors.

Beta-aminoisobutyric acid is a structural analog of gamma-aminobutyric acid (GABA; see 600233) and glycine, which are the major inhibitory neurotransmitters in the central nervous system. Additionally, beta-aminoisobutyric acid is a partial agonist of the glycine receptor (see 138491) (Schmieden et al., 1999). Van Kuilenburg et al. (2004) suggested that altered homeostasis of beta-aminoisobutyric acid in patients deficient in beta-ureidopropionase (606673) may underlie some of the clinical abnormalities in these individuals.

Molecular Genetics

In a genomewide association study of metabolic traits in human urine, Suhre et al. (2011) identified a SNP in the AGXT2 gene, rs37369 (612471.0001), as having the strongest association with urinary excretion of beta-aminoisobutyric acid. The SNP achieved a joint P value of 2.1 X 10(-182) in an initial study of 862 men in the population-based SHIP (Study of Health in Pomerania) study, with replication in 1,039 additional samples from the same study and 992 samples from both sexes from the independent KORA (Kooperative Gesundheitsforschung in der Region Augsburg) study. Suhre et al. (2011) noted that the product of the AGXT2 gene is a mitochondrial aminotransferase expressed primarily in the kidney that catalyzes the reaction of BAIB with pyruvate to form 2-methyl-3-oxopropanoate and alanine (EC 2.6.1.40). Given the exceptional strength of the association, Suhre et al. (2011) proposed that rs37369 is a likely candidate for the causative SNP of hyper-beta-aminoisobutyric aciduria.