Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany.
Blood. 2013 Aug 15;122(7):1312-5. doi: 10.1182/blood-2013-01-481499. Epub 2013 Jun 3.
To ascertain the genetic basis of a paroxysmal nocturnal hemoglobinuria (PNH) case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8-MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI anchor synthesis, whereas PIGT is essential for attachment of the preassembled GPI anchor to proteins. Although a single mutation event in the X-chromosomal gene PIGA is known to cause GPI-anchored protein deficiency, 2 such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells.
为了确定一例阵发性睡眠性血红蛋白尿症（PNH）病例的遗传基础，该病例在 PIGA 中没有体细胞突变，我们对糖基磷脂酰肌醇（GPI）锚定合成途径的所有已知基因的外显子进行了深度下一代测序。我们在 PIGT 中发现了一个杂合的胚系剪接位点突变，在粒细胞中发现了一个 8-MB 的体细胞缺失，影响了 PIGT 的另一个拷贝。PIGA 对于 GPI 锚定合成是必不可少的，而 PIGT 对于预先组装的 GPI 锚定与蛋白质的附着是必不可少的。虽然已知 X 染色体基因 PIGA 中的单个突变事件会导致 GPI 锚定蛋白缺乏，但在常染色体基因 PIGT 中需要 2 个这样的突变。我们的数据表明，即使在完全组装的 GPI 存在的情况下，如果其向造血干细胞中的蛋白质转移有缺陷，PNH 也可能发生。
