Kalaydjieva L, Perez-Lezaun A, Angelicheva D, Onengut S, Dye D, Bosshard N U, Jordanova A, Savov A, Yanakiev P, Kremensky I, Radeva B, Hallmayer J, Markov A, Nedkova V, Tournev I, Aneva L, Gitzelmann R
Centre for Human Genetics, Edith Cowan University, Joondalup Campus, Perth WA 6027, Australia.
Am J Hum Genet. 1999 Nov;65(5):1299-307. doi: 10.1086/302611.
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.
半乳糖激酶缺乏症是半乳糖代谢第一步中的一种先天性缺陷。其主要临床表现是在出生后的头几周内出现白内障。也有研究表明，该缺陷的携带者易患20至50岁之间出现的早老性白内障。新生儿筛查数据显示，全球范围内该基因频率非常低，但在欧洲罗姆人中较高。自1995年克隆半乳糖激酶基因（GK1）以来，仅发现了两个致病突变，且均局限于单个家族。在此，我们展示了对来自保加利亚的六个受影响的罗姆人家庭的研究结果，这些家庭中的索引患者是通过大规模筛查检测出患有半乳糖激酶缺乏症的。遗传连锁图谱将疾病位点定位在17号染色体长臂上，单倍型分析揭示了一个小的纯合保守区域。通过辐射杂种图谱分析，我们发现GK1基因位于该区域。本研究中鉴定出的罗姆人始祖突变是GK1基因中的一个单核苷酸替换，导致氨基酸位置28处保守的脯氨酸残基被苏氨酸取代（P28T）。在这个近亲通婚的群体中，P28T携带者率约为5%，这表明该突变可能是在有相当数量罗姆人少数群体的国家中导致幼儿失明的一个重要原因。
