Sommer M, Gathof B S, Podskarbi T, Giugliani R, Kleinlein B, Shin Y S
Medical Genetics Unit, HCPA, Porto Alegre, Brazil.
J Inherit Metab Dis. 1995;18(5):567-76. doi: 10.1007/BF02436001.
Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.
经典型半乳糖血症，即缺乏1-磷酸半乳糖尿苷转移酶（GALT），其特征为肝肿大、黄疸、败血症、白内障和生长发育迟缓等急性症状。通过限制饮食中的半乳糖进行治疗可立即纠正这些并发症；然而，这些儿童中的大多数会出现长期并发症，如言语失用症、智力迟钝和卵巢功能衰竭。我们之前的分子研究表明，在德国约60 - 65%的半乳糖血症患者群体中，GALT基因最常见的突变是Q188R错义突变（谷氨酰胺-188被精氨酸取代）。从经典型半乳糖血症个体（Q188R为阴性或杂合子）的基因组DNA中通过聚合酶链反应扩增GALT的编码区，并通过直接测序进一步进行特征分析。在两个患有轻度半乳糖血症变异型的家庭中的三名患者中鉴定出三个新的致病突变，两个错义突变和一个终止密码子突变：首先是R67C，一名男性中精氨酸-67被半胱氨酸取代以及W316X，色氨酸-316处的终止密码子；其次是A330V，两名女性同胞中丙氨酸-330被缬氨酸取代。在第一个家庭中，该患者也是多态性N314D的杂合子，在第二个家庭中，两个女孩都是Q188R和A330V的复合杂合子。所有三名半乳糖血症个体的红细胞中都有相当数量的残余GALT活性，并且治疗后1-磷酸半乳糖（GALP）水平下降速度比其他有错义突变如Q188R的半乳糖血症患者快得多。与两名半乳糖血症女性个体相比，这些患者的临床和生化数据要好得多，其中一名是L195P纯合子，另一名是Q188R和L195P复合杂合子。这三个错义突变（R67C、L195P和A330V）也出现在高度保守区域。这些观察结果表明，半乳糖血症个体的表型变异可能是由于不同的分子病因。
