Li W, Detter J C, Weiss H J, Cramer E M, Zhang Q, Novak E K, Favier R, Kingsmore S F, Swank R T
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
Mol Genet Metab. 2000 Dec;71(4):599-608. doi: 10.1006/mgme.2000.3091.
Hermansky-Pudlak syndrome (HPS) is a recessively inherited disease with dysfunction of several related subcellular organelles including platelet-dense granules, melanosomes, and lysosomes. Our recent identification of the mutation in murine Rab geranylgeranyl transferase alpha-subunit gene (Rabggta) in one mouse model of HPS, the gunmetal mouse, suggested that human patients with similar phenotypes might have mutations in the human orthologous RABGGTA gene. This prompted reanalysis of the 5'-untranslated structure of the human RABGGTA gene in normal individuals and in patients with deficiencies of platelet-dense granules (alphadelta-SPD), alpha granules (alpha-SPD or gray platelet syndrome, GPS) or alpha plus dense granules (alphadelta-SPD). We report the complete sequence of intron alpha of RABGGTA and demonstrate that exon alpha is immediately upstream of intron alpha. The exon/intron structural organization of the 5'-untranslated region (UTR) of human RABGGTA was found to be similar to that of the mouse Rabggta gene. However, exons alpha and introns alpha are not homologous between mouse and human. Features of the 5'-UTR of RABGGTA suggest it is a housekeeping gene. While obvious disease-causing mutations of human RABGGTA were not found in our existing SPD patients by sequencing its entire coding region, several polymorphisms of RABGGTA including a putative cryptic splicing mutation in intron 4 were identified. Knowledge of the 5'-UTR structure of RABGGTA and its common polymorphisms will be useful for mutation screening or linkage analysis in patients with albinism, thrombocytopenia, or platelet SPD.
Hermansky-Pudlak综合征（HPS）是一种隐性遗传性疾病，会导致包括血小板致密颗粒、黑素小体和溶酶体在内的几种相关亚细胞器功能障碍。我们最近在一种HPS小鼠模型——青灰小鼠中发现了鼠源Rab geranylgeranyl转移酶α亚基基因（Rabggta）的突变，这表明具有相似表型的人类患者可能在人类同源RABGGTA基因中存在突变。这促使我们重新分析正常个体以及血小板致密颗粒缺乏症（αδ-SPD）、α颗粒缺乏症（α-SPD或灰色血小板综合征，GPS）或α加致密颗粒缺乏症（αδ-SPD）患者中人类RABGGTA基因的5'-非翻译结构。我们报告了RABGGTA内含子α的完整序列，并证明外显子α紧邻内含子α的上游。发现人类RABGGTA的5'-非翻译区（UTR）的外显子/内含子结构组织与小鼠Rabggta基因相似。然而，小鼠和人类之间的外显子α和内含子α并不同源。RABGGTA的5'-UTR特征表明它是一个管家基因。虽然通过对现有SPD患者的人类RABGGTA整个编码区进行测序未发现明显的致病突变，但鉴定出了RABGGTA的几种多态性，包括内含子4中一个假定的隐蔽剪接突变。了解RABGGTA的5'-UTR结构及其常见多态性将有助于对白化病、血小板减少症或血小板SPD患者进行突变筛查或连锁分析。
