Luzi P, Rafi M A, Wenger D A
Departments of Medicine and Biochemstry and Molecular Biology, Thomas Jefferson University, Phildelphia, Pennsylvania, USA.
Hum Mol Genet. 1995 Dec;4(12):2335-8. doi: 10.1093/hmg/4.12.2335.
Globoid cell leukodystrophy (GLD) of Krabbe disease results from mutations in the galactocerebrosidase (GALC) gene. Previously, we had identified a large deletion in the GALC gene together with a C to T polymorphism at cDNA position 502 in a significant number of cases of infantile Krabbe disease; however, the deletion breakpoint had not been found. In this paper we show that the deletion is approximately 30 kb starting near the middle of the 12 kb intron 10, and includes all of the coding region through exon 17 plus an additional 9 kb. The deletion junction contains a 4 bp direct repeat and is preceded by sequence identified as belonging to the Alu family of interspersed repetitive elements. Using genomic DNA and a PCR-based test to detect normal and deleted sequences at that location, a large number of patients with all clinical types of GLD were analyzed. Of 21 infantile patients found to be heterozygous for the 502T polymorphism reported previously, 15 had the deletion, one could not tested and five, including a Hmong child, did not have the deletion. Sixteen other infantile patients previously tested were found to be either homozygous (10) or heterozygous (6) for the deletion. In addition, five patients with juvenile and adult GLD were found to be heterozygous for the deletion. In every case tested, the deletion was always found on the same allele as the 502T polymorphism. However, other disease-causing mutations have been found on the 502T allele. With careful genotype analysis these families can receive improved genetic information including patient and carrier identification and preimplantation diagnosis.
克拉伯病的球状细胞脑白质营养不良（GLD）是由半乳糖脑苷脂酶（GALC）基因突变引起的。此前，我们在大量婴儿型克拉伯病病例中发现了GALC基因的大片段缺失以及cDNA位置502处的C到T多态性；然而，缺失断点尚未找到。在本文中，我们表明该缺失约为30 kb，起始于12 kb内含子10的中部附近，包括外显子17之前的所有编码区以及另外9 kb。缺失连接处包含一个4 bp的直接重复序列，其前面是被鉴定为属于散布重复元件Alu家族的序列。使用基因组DNA和基于PCR的检测方法来检测该位置的正常和缺失序列，对大量所有临床类型的GLD患者进行了分析。在之前报告的21例婴儿患者中，发现他们对于502T多态性为杂合子，其中15例有该缺失，1例无法检测，5例（包括1名苗族儿童）没有该缺失。另外16例之前检测过的婴儿患者被发现对于该缺失为纯合子（10例）或杂合子（6例）。此外，发现5例青少年和成人GLD患者对于该缺失为杂合子。在每一例检测的病例中，缺失总是与502T多态性位于同一个等位基因上。然而，在502T等位基因上也发现了其他致病突变。通过仔细的基因型分析，这些家庭可以获得更完善的遗传信息，包括患者和携带者的鉴定以及植入前诊断。
