Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS.
Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS.
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DOI：
10.1016/j.ymgme.2017.02.007
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发表时间：
2017-04
影响因子：
3.8
通讯作者：
Gochuico BR
中科院分区：
文献类型：
--
作者：
Bryan MM;Tolman NJ;Simon KL;Huizing M;Hufnagel RB;Brooks BP;Speransky V;Mullikin JC;Gahl WA;Malicdan MCV;Gochuico BR
赫曼斯基-普德拉克综合征 (HPS) 是一种罕见的遗传性疾病，已报告有十种遗传类型；每种类型的衔接蛋白 3 复合体或溶酶体相关细胞器生物发生复合体 (BLOC)-1、-2 或 -3 的亚基都有缺陷。很少有 BLOC-1 缺乏症（HPS-7、-8 和 -9 型）患者被诊断出来。我们报告了来自新的 HPS-7 病例的原代成纤维细胞的综合临床测试和分子分析结果。一名 6 岁巴拉圭男性出现色素沉着不足、眼部白化病、眼球震颤、视力下降和容易瘀伤。当他很小的时候，他还经历了运动和语言发育迟缓的情况；头部和胸部创伤导致颅内出血，随后出现右侧偏瘫和肺部疤痕。没有免疫缺陷或结肠炎的临床证据。整体透射电子显微镜显示不存在血小板δ颗粒；血小板聚集检测异常。外显子组测序揭示了 Dystrobrevin 结合蛋白 1 (DTNBP1) 基因中存在纯合无义突变 [NM 032122.4: c.307C>T； p.Gln103*]，之前在葡萄牙成人中报道过。该基因编码 BLOC-1 的 Dysbindin 亚基。在该患者的真皮成纤维细胞中 Dysbindin 蛋白表达可以忽略不计，而他的 DTNBP1 mRNA 水平与正常对照相似。对报告的首例 HPS-7 儿科病例的综合临床评估显示眼皮肤白化病和血小板储存池缺陷；他的表型与其他 BLOC-1 疾病患者的发现一致。该患者的 HPS-7 中 Dysbindin 蛋白表达显着降低，这是由于无意义介导的衰变以外的机制造成的。
Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising. He also experienced delayed motor and language development as a very young child; head and chest trauma resulted in intracranial hemorrhage with subsequent right hemiparesis and lung scarring. There was no clinical evidence of immunodeficiency or colitis. Whole mount transmission electron microscopy revealed absent platelet delta granules; platelet aggregation testing was abnormal. Exome sequencing revealed a homozygous nonsense mutation in the Dystrobrevin binding protein 1 (DTNBP1) gene [NM 032122.4: c.307C>T; p.Gln103*], previously reported in a Portuguese adult. The gene encodes the dysbindin subunit of BLOC-1. Dysbindin protein expression was negligible in our patient’s dermal fibroblasts, while his DTNBP1 mRNA level was similar to that of a normal control. Comprehensive clinical evaluation of the first pediatric case reported with HPS-7 reveals oculocutaneous albinism and platelet storage pool deficiency; his phenotype is consistent with findings in other patients with BLOC-1 disorders. This patient’s markedly reduced Dysbindin protein expression in HPS-7 resulted from a mechanism other than nonsense mediated decay.