McInnes B, Potier M, Wakamatsu N, Melancon S B, Klavins M H, Tsuji S, Mahuran D J
Research Institute, Hospital for Sick Children, Montréal, Québec, Canada.
J Clin Invest. 1992 Aug;90(2):306-14. doi: 10.1172/JCI115863.
Sandhoff disease is caused by mutations affecting the beta subunit of lysosomal beta-hexosaminidase (EC 3.2.1.52) and displays a wide spectrum of clinical phenotypes. We report a 57-year-old patient with a very mild phenotype, although residual hexosaminidase A activity in his cultured fibroblasts was less than 3% of normal activity, a level observed in juvenile onset patients. Northern and Western blot analyses confirmed a similar low level of beta subunit-mRNA and mature beta-protein, respectively. Two mutations of the HEXB gene were identified in this patient, a partial 5' gene deletion (a null allele), and a C----T transition 8 nucleotides downstream from the intron 10/exon 11 junction affecting the splicing of the beta subunit-mRNA. In their homozygous forms, the 5' deletion has been previously shown to result in a severe infantile phenotype, and the C----T transition in a juvenile phenotype. The genotype and the low level of residual hexosaminidase A activity would be expected to produce a juvenile Sandhoff phenotype in this patient, as well as in four of his six clinically normal siblings. The biochemical basis of his mild phenotype is uncertain, but may result from genetic variations in the RNA splicing machinery.
桑德霍夫病由影响溶酶体β - 氨基己糖苷酶（EC 3.2.1.52）β亚基的突变引起，表现出广泛的临床表型。我们报告了一名57岁的患者，其表型非常轻微，尽管其培养的成纤维细胞中残余的氨基己糖苷酶A活性低于正常活性的3%，这一水平在青少年发病患者中可见。Northern印迹和Western印迹分析分别证实了β亚基 - mRNA和成熟β蛋白的水平同样较低。在该患者中鉴定出HEXB基因的两个突变，一个是5'基因部分缺失（无效等位基因），另一个是在第10内含子/第11外显子连接处下游8个核苷酸处的C→T转换，影响β亚基 - mRNA的剪接。5'缺失的纯合形式先前已显示会导致严重的婴儿型表型，而C→T转换则导致青少年型表型。预期该患者及其六个临床正常的兄弟姐妹中的四个，其基因型和残余氨基己糖苷酶A活性的低水平会产生青少年型桑德霍夫表型。其轻微表型的生化基础尚不确定，但可能是由于RNA剪接机制中的基因变异所致。
