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

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataract s in the first weeks of life. It has also been suggested that carriers of t he deficiency are predisposed to presenile cataracts developing at age 20-5 0 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 res ults of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass scree ning. Genetic linkage mapping placed the disease locus on 17q, and haplotyp e analysis revealed a small conserved region of homozygosity. Using radiati on hybrid mapping, we have shown that GK1 is located in this region. The fo under Romani mutation identified in this study is a single nucleotide subst itution in GK1 resulting in the replacement of the conserved proline residu e at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is similar to 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.