Chapter 8 - Primary Inherited Aminoacidurias: Genetic Defects in the Renal Handling of Amino Acids

Abstract

Primary inherited aminoacidurias (PIA) are caused by defective amino acid transport activities, which affect renal reabsorption of these compounds and may also affect their transport during intestinal absorption and in other organs as well. Plasma membrane transport of dibasic amino acids is abnormal in four inherited diseases that include cystinuria, lysinuric protein intolerance (LPI), autosomal dominant hyperdibasic aminoaciduria type I, and isolated lysinuria. Cystinuria and LPI are caused by defective amino acid transporter systems b0,+, and y+ L, respectively. These two transporters belong to the family of heteromeric amino acid transporters (HAT). Heteromeric amino acid transporters (HATs) are composed of a heavy subunit and a light subunit. These are unique features among mammalian plasma membrane amino acid transporters. Two homologous heavy subunits from the SLC3 family have been cloned, rBAT and 4F2hc. The transport characteristics of two HAT-associated transport systems are relevant to two PIA, which include cystinuria and LPI. Cystinuria is an autosomal inherited disorder, characterized by impaired transport of cystine and dibasic amino acids in the proximal renal tubule and the gastrointestinal tract. LPI is a primary inherited aminoaciduria with an autosomal recessive mode of inheritance predominantly reported in Finland where the prevalence of the disorder is 1 in 60,000. In LPI there is massive urinary excretion of dibasic amino acids, especially lysine, and the intestinal absorption of these amino acids is poor; therefore, the concentration of dibasic amino acids in plasma is low. Arginine and ornithine are intermediates of the urea cycle that provide the carbon skeleton to the cycle.