A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies)

Abstract

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is approximately 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.

Figure 1

Romani family with galactokinase deficiency. The proband P.P.V. (individual 4-3) was detected by the neonatal screening program, whereas the two affected cousins, K.N.S (individual 4-7) and K.P.T. (individual 4-11), were born before the initiation of the screening and after the discontinuation of its hypergalactosemia component, respectively. Individual 4-5 reported a history of infantile cataracts and was found to be homozygous for the P28T mutation; her erythrocyte galactokinase activity was in the intermediate range.

Figure 2

Marker haplotypes in the 17q24 region of disease chromosomes from Gypsy families with galactokinase deficiency. Radiation-hybrid mapping (high-resolution TNG panel) placed the GK1 gene in very close proximity to D17S1839.

Figure 3

Secondary-structure prediction for the wild-type galactokinase protein and the V32M and P28T mutants, using the PHDsec algorithm. A selection of the first 60 amino acids is shown. E=extended sheet (beta sheet); H=helix; L=loop. The prediction is meaningful for all residues with an expected average correlation >.69.