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.

Angiotensin-converting enzyme deletion allele is beneficial for the longevity of Europeans

“…Genomic DNA was amplified by polymerase chain reaction (PCR) with primers 5′-CTG GAG ACC ACT CCC ATC CTT TCT-3′ (forward) and 5′-GAT GTG GCC ATC ACA TTC GTC AGA T-3′ (reverse). PCR cycling was in a touchdown regime described previously (Kalaydjieva et al 1999).…”

Vlax Roma history: what do coalescent-based methods tell us?

“…Interest in the genetics of the Vlax Roma has resulted in the identification of several novel single gene disorders and private founder mutations, Hereditary Motor and Sensory Neuropathy types Lom 4,5 and Russe, 6,7 Congenital Cataracts Facial Dysmorphism Neuropathy Syndrome 8,9 and galactokinase deficiency. 10,11 A population genetic study of three groups of Vlax Roma 12 revealed limited diversity, with a single ancestral Y chromosome lineage shared by 73% of males. The Vlax Roma, who account for a substantial proportion of the overall Gypsy population, thus qualify among the most restricted founder popula-tions of Europe whose potential for the study of genetically complex disorders is still to be explored.…”

Newborn Screening for Galactosemia in the United States: Looking Back, Looking Around, and Looking Ahead

“…GALK deficiency is diagnosed in (<1/100,000) US newborns but may be more common in some populations (e.g., the Romani) (Hennermann et al 2011;Janzen et al 2011;Kalaydjieva et al 1999;Sangiuolo et al 2004). …”