A Genetic Factor for Age-Related Cataract: Identification and Characterization of a Novel Galactokinase Variant, “Osaka,” in Asians

Abstract

Galactokinase (GALK) deficiency is an autosomal recessive disorder characterized by hypergalactosemia and cataract formation. Through mass screening of newborn infants, we identified a novel and prevalent GALK variant (designated here as the "Osaka" variant) associated with an A198V mutation in three infants with mild GALK deficiency. GALK activity and the amount of immunoreactive protein in the mutant were both 20% of normal construct in expression analysis. The K(m) values for galactose and ATP-Mg(2+) in erythrocytes with homozygous A198V were similar to those of the healthy adult control subjects. A population study for A198V revealed prevalences of 4.1% in Japanese and 2.8% in Koreans, lower incidence in Taiwanese and Chinese, no incidence in blacks and whites from the United States, and a significantly high frequency (7.8%; P < .023) in Japanese individuals with bilateral cataract. This variant probably originated in Japanese and Korean ancestors and is one of the genetic factors that causes cataract in elderly individuals.

Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados

“…Individuals heterozygous for galactokinase deficiency are at increased risk for presenile cataracts, whereas at least one GALK1 allele results in 20% residual activity due to a shortened protein half-life. This allele, the Osaka variant, increases risk of age-related cataracts in Japanese populations (26,27).…”

Molecular Structure of Human Galactokinase

“…One of these mutant proteins, A198V, is soluble on expression in E. coli and has kinetic parameters, which are essentially indistinguishable from the wild-type (24). In contrast with the other mutations, where cataract formation is a near certainty within the first few years of life, this mutation merely results in a higher incidence of cataracts in later life (41). Ala 198 resides in a ␤-strand and is ϳ17 Å from the active site.…”

Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q

“…23 -26 In addition, five genes for lens membrane/cytoskeletal proteins includ-ing those for connexin50 (GJA8) on 1q, 27 -29 connexin46 (GJA3) on 13q, 30,31 aquaporin-0 (MIP) on 12q, 32 a peripheral myelin-like protein (LIM2) on 19q 33 and an intermediate filament-like protein (BFSP2) on 3q 34,35 have been linked with Mendelian cataract. Moreover, certain mutations in genes widely expressed outside the lens, including those for paired-like homeodomain transcription factor 3 (PITX3) on 10q, 36 heat-shock transcription factor 4 (HSF4) on 16q, 37 galactokinase 1 (GALK1) on 17q 38 and L-ferritin (FTL) on 19q, 39 have been associated with cataract in the absence of other significant ocular or systemic defects. To gain further insight about the pathogenetic complexity of hereditary cataract, we have carried out linkage analysis in a family segregating autosomal dominant 'nuclear' cataract and subsequently identified a novel missense mutation in the gene for alphaA-crystallin (CRYAA) on 21q, which encodes a member of the small-heat-shock protein (sHSP) family of molecular chaperones.…”