Vallance Hilary, Morris Tara J, Coulter-Mackie Marion, Lim-Steele Joyce, Kaback Michael
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada V6H 3N1.
Mol Genet Metab. 2006 Feb;87(2):122-7. doi: 10.1016/j.ymgme.2005.10.012. Epub 2005 Dec 13.
A DNA-proven Tay-Sachs disease (TSD) carrier and his brother were found to have serum percent Hexosaminidase A (%HexA) enzymatic activities in the non-carrier range, while the leukocyte %HexA profiles clearly identified them as TSD heterozygotes. Both their serum HexA and HexB enzymatic activities were below reference range, suggesting inheritance of mutations in both the HEXA (alpha-subunit) and HEXB (beta-subunit) genes. DNA sequencing revealed that both individuals, carried the common HEXA 1277_1278insTATC mutation, and two common HEXB polymorphisms: [619A>G (+) delTG]. To determine if these HEXB polymorphisms reduce HexA and HexB enzymatic activities, 69 DNA samples from subjects previously screened enzymatically in both serum and leukocytes for TSD carrier status were selected for either high, mid-range or low serum Total Hex (defined as the sum of HexA and HexB) activities and were tested for the HEXB mutations. Further, three additional TSD carriers ascertained by the atypical pattern of normal serum %HexA but carrier leukocyte %HexA, were found to have the [delTG (+) 619A>G] genotype. In addition, the frequency of the [delTG (+) 619A>G] genotype was significantly higher (P < 0.01) in subjects with low serum HexB enzymatic activities. Given the high frequency of the [delTG (+) 619A>G] haplotype in the Ashkenazi Jewish population (approximately 10%), up to 10% of TSD carriers may have normal serum %HexA values with low total Hex. Accordingly, serum %HexA should not be the sole criterion used for carrier status determination. Where total Hex activity is reduced, further testing with leukocyte Hex profiles is indicated.
一名经DNA检测证实的泰-萨克斯病（TSD）携带者及其兄弟的血清己糖胺酶A（%HexA）酶活性处于非携带者范围内，而白细胞%HexA谱则明确将他们鉴定为TSD杂合子。他们的血清HexA和HexB酶活性均低于参考范围，提示HEXA（α亚基）和HEXB（β亚基）基因均发生了突变遗传。DNA测序显示，这两人均携带常见的HEXA 1277_1278insTATC突变以及两种常见的HEXB多态性：[619A>G(+)delTG]。为确定这些HEXB多态性是否会降低HexA和HexB酶活性，从之前在血清和白细胞中进行过TSD携带者状态酶学筛查的受试者中选取了69份DNA样本，这些样本的血清总己糖（定义为HexA和HexB之和）活性分别为高、中、低水平，并对其进行HEXB突变检测。此外，通过血清%HexA正常但白细胞%HexA呈携带者模式这种非典型模式确定的另外三名TSD携带者，被发现具有[delTG(+)619A>G]基因型。此外，血清HexB酶活性低的受试者中，[delTG(+)619A>G]基因型的频率显著更高（P<0.01）。鉴于德系犹太人群中[delTG(+)619A>G]单倍型的频率较高（约10%）,高达10%的TSD携带者可能血清%HexA值正常但总己糖水平较低。因此，血清%HexA不应作为确定携带者状态的唯一标准。当总己糖活性降低时，建议进一步检测白细胞己糖谱。
