Phenylalanine metabolism and "phenylketonuria" in dilute-lethal mice.

M I C E homozygous for the dilute-lethal (8) gene have been reported by COLEMAN (1960) and RAUCH and YOST (1963) to have low liver phenylalanine hydroxylase activity. This deficiency in phenylalanine metabolism has been reported to be due to the presence of an inhibitor of the hydroxylase localized in a particulate fraction of liver (15,000 x g sediment). These investigators have pointed out that the enzymatic deficiency and several neurological disturbances of dilute-lethal homozygotes resemble phenylketonuria in humans. The condition is inherited as an autosomal Mendelian recessive character. The mice are normal at birth, but opisthotonic seizures appear when about 14 days old and occur with increased frequency and severity until death at about 3 weeks of age. KELTON and RAUCH (1962) report that myelin formation is initially normal but myelin degeneration occurs shortly therea€ter, a few days before the onset of the abnormal neurological signs and continues until death. The hair of dilute-lethal homozygotes is also pale as in homozygotes for the nonlethal dilute (d ) allele. This dilution is apparently due to the abnormal clumping of melanin granules around the nucleus rather than a reduction in the amount of pigment ( MARKERT and SILVERS 1956). Further investigations with these animals, as a model of experimental phenylketonuria, are of considerable interest in studying the relationship between the biochemical disturbances and the central nervous system pathology in phenylketonuria. This paper presents comparative biochemical studies using stocks of three independent dilute-lethal mutations. The concentration of phenylalanine in blood, phenylpyruvic acid excreted in urine and liver phenylalanine hydroxylase activity are compared. Differences in susceptibility of liver phenylalanine hydroxylase to inhibition by L-phenylalanine and phenylpyruvic acid will be described. A preliminary report of this work has been presented (WEBER, VAN VALEN, LA Du and ZANNONI 1965).