Homozygosity mapping and whole-exome sequencing to detect SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia.
Homozygosity mapping and whole-exome sequencing to detect SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia.
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DOI：
10.1038/jid.2011.157
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发表时间：
2011-10
影响因子：
6.5
通讯作者：
Gahl, William A.
中科院分区：
文献类型：
--
作者：
Cullinane, Andrew R.;Vilboux, Thierry;O'Brien, Kevin;Curry, James A.;Maynard, Dawn M.;Carlson-Donohoe, Hannah;Ciccone, Carla;Markello, Thomas C.;Gunay-Aygun, Meral;Huizing, Marjan;Gahl, William A.
我们评估了一位32岁的女性，她的眼皮肤白化、出血素质、中性粒细胞减少和反复感染的病史促使我们考虑诊断为Hermansky-Pudlak综合征2型(HPS-2)。由于存在血小板三角洲颗粒和没有AP3B1突变，因此排除了这一可能性。由于亲本血缘关系提示常染色体隐性遗传方式，我们采用纯合子作图和外显子全序列测序的方法，确定了两个候选致病基因SLC45A2和G6PC3。常规的二脱氧测序证实了SLC45A2和G6PC3的致病突变，SLC45A2与眼皮肤白化病4型(OCA-4)相关，G6PC3与中性粒细胞减少相关。患者黑素细胞中SLC45A2蛋白的大幅减少导致酪氨酸酶从黑素体到质膜的错位，也导致酪氨酸酶并入外切体和分泌到培养基中，解释了OCA-4的色素降低。我们的患者G6PC3mRNA表达水平也降低，导致内质网应激下HER成纤维细胞凋亡率增加。这份报告描述了第一例患有OCA-4的北美患者，这是第一次培养人类OCA-4黑素细胞，并使用纯合性图谱和整个外显子组测序来识别单个受影响个体的多个基因的致病突变。
We evaluated a 32 year-old woman whose oculocutaneous albinism, bleeding diathesis, neutropenia, and history of recurrent infections prompted consideration of the diagnosis of Hermansky-Pudlak syndrome type 2 (HPS-2). This was ruled out due to the presence of platelet delta granules and absence of AP3B1 mutations. Since parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping, followed by whole exome sequencing, to identify two candidate disease-causing genes, SLC45A2 and G6PC3. Conventional di-deoxy sequencing confirmed pathogenic mutations in SLC45A2, associated with oculocutaneous albinism type 4 (OCA-4), and G6PC3, associated with neutropenia. The substantial reduction of SLC45A2 protein in the patient’s melanocytes caused the mis-localization of tyrosinase from melanosomes to the plasma membrane and also led to the incorporation of tyrosinase into exosomes and secretion into the culture medium, explaining the hypopigmentation in OCA-4. Our patient’s G6PC3 mRNA expression level was also reduced, leading to increased apoptosis of her fibroblasts under ER stress. This report describes the first North American patient with OCA-4, the first culture of human OCA-4 melanocytes, and the use of homozygosity mapping followed by whole exome sequencing to identify disease-causing mutations in multiple genes in a single affected individual.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.6
作者：
PIGAULT, C;FOLLENIUSWUND, A;BRISSON, A
通讯作者：
BRISSON, A
影响因子：
3.7
作者：
通讯作者：
--
影响因子：
158.5
作者：
BONILLA, MA;GILLIO, AP;OREILLY, RJ
通讯作者：
OREILLY, RJ
影响因子：
16
作者：
Dell'Angelica, EC;Shotelersuk, V;Bonifacino, JS
通讯作者：
Bonifacino, JS