Tatsumi N, Inui K, Sakai N, Fukushima H, Nishimoto J, Yanagihara I, Nishigaki T, Tsukamoto H, Fu L, Taniike M
Department of Pediatrics, Faculty of Medicine, Osaka University, Japan.
Hum Mol Genet. 1995 Oct;4(10):1865-8. doi: 10.1093/hmg/4.10.1865.
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous systems due to an enzymatic defect of the galactocerebrosidase. In this study, molecular defects in Krabbe disease were investigated in 11 patients (seven Japanese and four non-Japanese) using cultured skin fibroblasts. A Japanese late infantile patient had a missense mutation of Pro at codon 302 to Ala and a non-Japanese patient had a missense mutation of Val at codon 550 to Gly. The reduced enzymatic activities expressed from the cDNAs with these missense mutations and from the previously reported nonsense mutation (E369X, Glu at codon 369 to stop codon) were confirmed. Genomic DNA analyses revealed that the P302A and E369X mutations were heterozygous and the V550G mutation was homozygous in these patients. A 12 base deletion with a 3 base insertion was found in three unrelated Japanese infantile patients, but not in 30 controls. The mutation was homozygous in two patients and heterozygous in one patient. We could not find any confirmed mutation in the coding region in the other six patients. These findings suggest that mutations in infantile and late infantile patients are relatively heterogeneous.
克拉伯病（球状细胞脑白质营养不良）是一种常染色体隐性神经退行性疾病，由于半乳糖脑苷脂酶的酶缺陷，会影响中枢和周围神经系统。在本研究中，我们使用培养的皮肤成纤维细胞对11名患者（7名日本患者和4名非日本患者）的克拉伯病分子缺陷进行了研究。一名日本晚发性婴儿患者在密码子302处发生脯氨酸错义突变为丙氨酸，一名非日本患者在密码子550处发生缬氨酸错义突变为甘氨酸。携带这些错义突变的cDNA以及先前报道的无义突变（E369X，密码子369处的谷氨酸突变为终止密码子）所表达的酶活性降低得到了证实。基因组DNA分析显示，这些患者中P302A和E369X突变为杂合子，V550G突变为纯合子。在3名不相关的日本婴儿患者中发现了12个碱基缺失并伴有3个碱基插入，但在30名对照中未发现。该突变在两名患者中为纯合子，在一名患者中为杂合子。我们在其他6名患者的编码区未发现任何已确认的突变。这些发现表明，婴儿型和晚发性婴儿型患者的突变相对异质性。
