Errors Congènits del Metabolisme-IBC, Serv. Bioquímica i Genètica Molecular, Hospital Clínic, Barcelona, Spain.
Gene. 2012 Sep 10;506(1):25-30. doi: 10.1016/j.gene.2012.06.080. Epub 2012 Jul 10.
The GM2 gangliosidoses are autosomal recessive lysosomal storage diseases caused by a deficiency of the β-hexosaminidase A enzyme. This enzyme is composed of two polypeptide chains designated the α- and β- subunits and it interacts with the GM2 activator protein. The HEXA and HEXB genes encode the α-subunit and the β-subunit, respectively. Mutations in these genes are causative of Tay-Sachs disease (HEXA) and Sandhoff disease (HEXB). We analyzed the complete HEXA gene in 34 Spanish patients with Tay-Sachs disease and the HEXB gene in 14 Spanish patients with Sandhoff disease. We identified 27 different mutations, 14 of which were novel, in the HEXA gene and 14 different mutations, 8 of which unreported until now, in the HEXB gene, and we attempted to correlate these mutations with the clinical presentation of the patients. We found a high frequency of c.459+5G>A (IVS4+5G>A) mutation in HEXA affected patients, 22 of 68 alleles, which represent the 32.4%. This is the highest percentage found of this mutation in a population. All patients homozygous for mutation c.459+5G>A presented with the infantile form of the disease and, as previously reported, patients carrying mutation p.R178H in at least one of the alleles presented with a milder form. In HEXB affected patients, the novel deletion c.171delG accounts for 21.4% of the mutant alleles (6/28). All patients with this deletion showed the infantile form of the disease. The Spanish GM2 gangliosidoses affected patients show a great mutational heterogeneity as seen in other inherited lisosomal diseases in this country.
GM2 神经节苷脂贮积症是一种常染色体隐性溶酶体贮积病，由β-己糖胺酶 A 酶缺乏引起。该酶由两条多肽链组成，分别命名为α-和β-亚单位，并与 GM2 激活蛋白相互作用。HEXA 和 HEXB 基因分别编码α-亚单位和β-亚单位。这些基因的突变是导致泰萨二氏病（HEXA）和桑格夫病（HEXB）的原因。我们分析了 34 名西班牙泰萨二氏病患者的完整 HEXA 基因和 14 名西班牙桑格夫病患者的 HEXB 基因。我们在 HEXA 基因中发现了 27 种不同的突变，其中 14 种是新的，在 HEXB 基因中发现了 14 种不同的突变，其中 8 种是以前没有报道过的，我们试图将这些突变与患者的临床表现相关联。我们发现，在受 HEXA 影响的患者中，c.459+5G>A（IVS4+5G>A）突变的频率很高，在 68 个等位基因中，占 22 个，代表 32.4%。这是该突变在人群中发现的最高比例。所有纯合 c.459+5G>A 突变的患者均表现为婴儿型疾病，正如先前报道的，至少有一个等位基因携带 p.R178H 突变的患者表现为较轻的形式。在 HEXB 受影响的患者中，新的缺失 c.171delG 占突变等位基因的 21.4%（6/28）。所有携带该缺失的患者均表现为婴儿型疾病。西班牙 GM2 神经节苷脂贮积症患者表现出与该国其他遗传性溶酶体疾病一样的巨大突变异质性。
