Blanch L, Weber B, Guo X H, Scott H S, Hopwood J J
Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, Australia.
Hum Mol Genet. 1997 May;6(5):787-91. doi: 10.1093/hmg/6.5.787.
Sanfilippo A syndrome (mucopolysaccharidosis type IIIA, MPS-IIIA) is an autosomal recessive neurodegenerative disorder due to an enzymatic defect of the lysosomal enzyme sulphamidase (EC 3.10.1.1) required for the degradation of heparan sulphate. In this study, molecular defects in the sulphamidase gene of MPS-IIIA patients were investigated in a group of 10 patients of Australian and American origin. The entire coding region of the sulphamidase gene was RT-PCR amplified and one polymorphism (R456H), four novel mutations (S66W, R245H, E447K, 1307 del 9) and one previously described mutation (1284 del 11) were identified by direct PCR sequencing. R245H was present in six patients including one severely affected homozygote. In three of the other patients with R245H, second mutant alleles were identified as S66W, 1284 del 11 and E447K, respectively. S66W was also detected in another patient where the other mutant allele remains undefined. In addition, 1307 del 9 was also detected in a patient with the other mutant allele remaining undefined. Allele specific oligonucleotide hybridisation was used to determine the incidence of these in a population of 26 MPS-IIIA patients (Australian and American) and 60 normal controls (Australian). R245H represented 27% (14/52 alleles) in this total patient population, while the other three changes ranged from 1.9 to 9.6% (1-5 of 52 alleles). The sequence variant, R456H, was shown to be polymorphic as it was present in 55% of normal and 38% of patient alleles. The total combined incidence of these five is 46% of alleles. This is the first study of the molecular defects in MPS-IIIA patients and will greatly assist the development of molecular analysis for MPS-IIIA patients and studies concerned with genotype to phenotype relationships.
桑菲利波综合征A（ⅢA型黏多糖贮积症，MPS-IIIA）是一种常染色体隐性神经退行性疾病，因溶酶体酶硫酸酰胺酶（EC 3.10.1.1）存在酶缺陷，该酶是降解硫酸乙酰肝素所必需的。在本研究中，对一组10名澳大利亚和美国裔的MPS-IIIA患者的硫酸酰胺酶基因分子缺陷进行了调查。通过逆转录聚合酶链反应（RT-PCR）扩增硫酸酰胺酶基因的整个编码区，并通过直接PCR测序鉴定出一个多态性位点（R456H）、四个新突变（S66W、R245H、E447K、1307 del 9）和一个先前描述的突变（1284 del 11）。R245H存在于6名患者中，包括1名严重受累的纯合子。在其他3名携带R245H的患者中，分别鉴定出第二个突变等位基因为S66W、1284 del 11和E447K。在另一名患者中也检测到S66W，其另一个突变等位基因尚未确定。此外，在另一名患者中也检测到1307 del 9，其另一个突变等位基因也未确定。采用等位基因特异性寡核苷酸杂交法，在26名MPS-IIIA患者（澳大利亚和美国）和60名正常对照（澳大利亚）群体中确定这些突变的发生率。在整个患者群体中，R245H占27%（52个等位基因中的14个），而其他三个变化范围为1.9%至9.6%（52个等位基因中的1 - 5个）。序列变异R456H显示为多态性，因为它存在于55%的正常等位基因和38%的患者等位基因中。这五个突变的总合并发生率为等位基因的46%。这是对MPS-IIIA患者分子缺陷的首次研究，将极大地有助于MPS-IIIA患者的分子分析以及与基因型-表型关系相关的研究。
