Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency
Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency
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DOI：
10.1086/324168
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发表时间：
2001-11-01
影响因子：
9.8
通讯作者：
Gahl, WA
中科院分区：
文献类型：
--
作者：
Huizing, M;Anikster, Y;Gahl, WA
Hermansky-Pudlak综合征（HPS）由皮肤白化病和血小板致密颗粒缺失引起的出血特征组成，表现出广泛的位点异质性。HPS1突变导致HPS-1疾病，ADTB3A突变导致HPS-2疾病，已知HPS-2与细胞内异常囊泡形成有关。根据波多黎各中部HPS遗传分离物的纯合子作图，最近确定了第三个HPS致病基因HPS3。我们现在描述了8名非波多黎各血统的HPS-3患者的临床和分子特征。5人是德系犹太人；其中三个是1303+1G - bbbba剪接位点突变的纯合子，该突变导致外显子5跳跃，删除RsaI限制位点并减少northern blotting上发现的mRNA数量。另外两个是杂合的1303+1G ->A突变和1831+2T ->G或2621-2A ->G剪接突变。在235个匿名德系犹太人DNA样本中，有一个是杂合的1303+1G ->A突变。一名来自德国/瑞士的7岁男孩的2729+1G—>C突变是复合杂合的，导致外显子14的跳跃，并导致C1329T错义（R396W）， mRNA产量减少。一名15岁的爱尔兰/英国男孩因异常剪接导致外显子16和17之间有89 bp的插入而杂合；成纤维细胞HPS3 mRNA量正常，但体积增大。一名波多黎各和意大利背景的12岁女孩在一个等位基因上有来自波多黎各中部的3904 bp的创始人缺失。所有8名患者都有轻微的HPS症状；两名犹太病人被诊断为眼部白化病，而不是眼皮肤白化病。这些发现扩大了HPS的分子诊断，为犹太人中常见的突变提供了一种筛查方法，并建议其他轻度色素沉着和视力下降的患者应检查HPS。
Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G -->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G -->A mutation and for either an 1831+2T -->G or a 2621-2A -->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G -->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G -->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.