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In a pedigree developed from affected Abyssinian cats, an early onset rod-cone dysplasia (Rdy) was identified and demonstrates an autosomal dominant inheritance. This is an excellent model for inhe...

White fur or coat pigmentation and the presence of blue eyes have been linked to cochleosaccular deafness in multiple mammalian species. At this time, no hereditary explanation has been presented for this phenotype as it appears in horses. A candidate gene study was established to determine the genetic basis for this disorder in a pedigree of Spanish Mustangs. KIT, a receptor tyrosine kinase implicated in multiple mammalian deafness studies, was sequenced in both the affected Spanish Mustangs and related members of the pedigree. A mutation (KI16 + 1037A) in the 5’ splice junction of exon 17 known to cause the sabino coat pattern appeared to be unlinked from the deafness phenotype. Sabino coloration is distinguished as a white coat, ranging from minimal white splashes to an entirely white mammal. Future research will focus on the sequencing of additional candidate genes affecting melanocyte migration and melanin production, including EDNRB, MITF, PMEL17, and SOX10.Grant Funding Source: Supported by HHMI

Recently, Knappe and co-workers [Knappe, J., Neugebauer, F. A., Blaschkowski, H. P., & Ganzler, M. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 1332] have shown that the catalytically active form of pyruvate formate-lyase from Escherichia coli is associated with a protein-bound organic free radical which is quenched upon enzyme inactivation by oxygen or hypophosphite. Our interest in the chemical mechanism of this unusual enzymatic reaction has led us to investigate several key aspects of the inactivation of the lyase by hypophosphite and its relationship to the normal enzymatic reaction. We report here that the inactivation of both the free and acetylated forms of the lyase is subject to a primary kinetic isotope effect using [2H2]hypophosphite. This suggests that phosphorus-hydrogen bond cleavage is at least partially rate limiting during inactivation. In addition, the inactivated enzyme can be fully reactivated. We have also determined a Vmax/Km isotope effect of 3.6 +/- 0.7 for pyruvate formation from [2H]formate and acetyl coenzyme A. Thus, carbon-hydrogen bond cleavage is partially rate limiting in the normal reverse reaction. On the basis of our findings, the previous work of Knappe and co-workers, the likelihood that hypophosphite is a formate analogue, the known susceptibility of both hypophosphite and formate to homolysis, and a chemical precedent for homolytic cleavage of pyruvate, we offer a preliminary mechanistic proposal for the lyase reaction.