Xu Chengzhe, Sakai Norio, Taniike Masako, Inui Koji, Ozono Keiichi
Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Hum Genet. 2006;51(6):548-554. doi: 10.1007/s10038-006-0396-3. Epub 2006 Apr 11.
Krabbe disease is an autosomal recessive leukodystrophy. It is pathologically characterized by demyelination of the central and peripheral nervous systems and the accumulation of globoid cells in brain white matter. It is caused by a deficiency of galactocerebrosidase (GALC) activity. We investigated mutations of the GALC gene in 17 Japanese patients with Krabbe disease, the largest subject number of Japanese patients to date, and found 27 mutations. Of these mutations, six were novel, including two nonsense mutations, W115X and R204X, two missense mutations, S257F and L364R, a small deletion, 393delT, and a small insertion, 1719-1720insT. Our findings, taken with the reported mutations in Japanese patients, confirm several mutations common to Japanese patients, the two most frequent being 12Del3Ins and I66M+I289V, which account for 37% of all mutant alleles. With two additional mutations, G270D and T652P, these account for up to 57% of genetic mutations in Japanese patients. Distribution of the mutations within the GALC gene indicated some genotype-phenotype correlation. I66M+I289M, G270D, and L618S contributed to a mild phenotype. Screening for these mutations may provide an effective method with which to predict the clinical phenotype.
克拉伯病是一种常染色体隐性白质营养不良症。其病理特征为中枢和周围神经系统脱髓鞘以及脑白质中出现球状细胞堆积。它是由半乳糖脑苷脂酶（GALC）活性缺乏引起的。我们对17例日本克拉伯病患者（这是迄今为止日本患者数量最多的研究对象）的GALC基因进行了突变研究，发现了27种突变。在这些突变中，有6种是新发现的，包括两个无义突变W115X和R204X、两个错义突变S257F和L364R、一个小缺失393delT以及一个小插入1719 - 1720insT。我们的研究结果与已报道的日本患者突变情况相结合，证实了日本患者中几种常见的突变，其中最常见的两种是12Del3Ins和I66M + I289V，它们占所有突变等位基因的37%。再加上另外两个突变G270D和T652P，这些突变在日本患者的基因突变中占比高达57%。GALC基因内突变的分布表明存在一些基因型 - 表型相关性。I66M + I289M、G270D和L618S导致较轻的表型。对这些突变进行筛查可能为预测临床表型提供一种有效的方法。
