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 ∼5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.
Hereditary motor and sensory neuropathy type Lom, initially identified in Roma (Gypsy) families from Bulgaria, has been mapped to 8q24. Further refined mapping of the region has been undertaken on ...DNA from patients diagnosed across Europe. The refined map consists of 25 microsatellite markers over approximately 3 cM. In this collaborative study we have identified a number of historical recombinations resulting from the spread of the hereditary motor and sensory neuropathy type Lom gene through Europe with the migration and isolation of Gypsy groups. Recombination mapping and the minimal region of homozygosity reduced the original 3 cM hereditary motor and sensory neuropathy type Lom region to a critical interval of about 200 kb.
In this study, we describe the molecular cloning and characterization of a Src‐like adaptor protein gene embedded within the genomic organization of the human thyroglobulin (Tg) gene. This gene was ...identified by exon trapping on overlapping cosmids encompassing the largest Tg intron. A 2.6‐kb transcript, with the highest levels of expression in fetal brain and lung, was detected on Northern blots. Two full‐length cDNAs (one alternatively spliced) were isolated from a fetal brain library, both containing an open reading frame of 276 amino acids, but lacking a catalytic tyrosine kinase domain. The gene shows a high degree of cross‐species similarity and appears to be transcribed in the direction opposite to Tg. This gene, designated hslap, appears to be the human ortholog of the recently described gene for the murine Src‐like adaptor protein (mSLAP), a candidate intermediate in the signal‐transduction pathway of the Eck receptor tyrosine kinase. Human slap is located in the candidate region for a recessive demyelinating neuropathy on chromosome 8q24, but sequence analysis failed to identify mutations, suggesting that it is not the gene for this disease.
PDF
