Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population
Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population
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DOI：
10.1186/1750-1172-7-44
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发表时间：
2012-06-26
影响因子：
3.7
通讯作者：
Ahmed, Zubair M.
中科院分区：
文献类型：
--
作者：
Jaworek, Thomas J.;Kausar, Tasleem;Ahmed, Zubair M.
背景资料：眼皮肤白化病（OCA）是由一组遗传异质性遗传缺陷引起的，导致眼睛，皮肤和头发色素沉着的丧失。TYR、OCA 2、TYRP 1和SLC 45 A2基因突变已被证明可引起孤立性OCA。没有进行全面的分析，以研究在巴基斯坦白化病populations.Methods的OCA等位基因的频谱：我们招募了40个大的巴基斯坦家庭，并筛选他们的OCA基因和候选基因，SLC 24 A5。使用计算机模拟预测算法和人黑素细胞中的离体研究评价蛋白质功能效应。结果：在10个家系中发现4个已知突变（p.Arg299His，p.Pro406Leu，p.Gly419Arg，p.Arg278*）和3个新突变（p.Pro21Leu，p.Cys35Arg，p.Tyr411His）。离体研究显示，在37 ℃下，EGFP标记的突变体（p.Pro21Leu、p.Cys35Arg或p.Tyr411His）酪氨酸酶保留在内质网（ER）中，但在允许温度（31 ℃）下生长的细胞中，显著部分的p.Cys35Arg和p.Tyr411His离开ER。在14个家系中发现3个新突变（p.Asp486Tyr，p.Leu527Arg，c.1045-15 T > G）和2个已知突变（p.Pro743Leu，p.Ala787Thr）。外显子捕获分析含有一个新的c.1045-15 T > G突变的构建体揭示了剪接错误。其余16个家系均未发现TYRP 1、SLC 45 A2和SLC 24 A5突变。对分离TYR或OCA 2突变的家族的临床评价显示眼球震颤、恐惧症和皮肤或毛囊色素沉着的丧失。大多数受影响的个人有灰蓝色coloredeyes.Conclusions：我们的研究结果表明，10个和14个家庭窝藏在TYR和OCA 2基因突变，分别。我们的研究结果，沿着与以前的研究结果，表明p.Cys35 Arg，p.Arg278* 和p.Gly419 Arg等位基因的TYR和p.Asp486 Tyr和c.1045-15 T > G等位基因的OCA在巴基斯坦家庭中是最常见的原因。据我们所知，这项研究代表了巴基斯坦人群中OCA 2等位基因的第一个文件。我们的队列中有很大一部分人在已知的OCA基因中没有突变。总的来说，我们的研究有助于在巴基斯坦家庭中发展OCA的基因检测方案和遗传咨询。
Background: Oculocutaneous albinism (OCA) is caused by a group of genetically heterogeneous inherited defects that result in the loss of pigmentation in the eyes, skin and hair. Mutations in the TYR, OCA2, TYRP1 and SLC45A2 genes have been shown to cause isolated OCA. No comprehensive analysis has been conducted to study the spectrum of OCA alleles prevailing in Pakistani albino populations.Methods: We enrolled 40 large Pakistani families and screened them for OCA genes and a candidate gene, SLC24A5. Protein function effects were evaluated using in silico prediction algorithms and ex vivo studies in human melanocytes. The effects of splice-site mutations were determined using an exon-trapping assay.Results: Screening of the TYR gene revealed four known (p.Arg299His, p.Pro406Leu, p.Gly419Arg, p.Arg278*) and three novel mutations (p.Pro21Leu, p.Cys35Arg, p.Tyr411His) in ten families. Ex vivo studies revealed the retention of an EGFP-tagged mutant (p.Pro21Leu, p.Cys35Arg or p.Tyr411His) tyrosinase in the endoplasmic reticulum (ER) at 37 degrees C, but a significant fraction of p.Cys35Arg and p.Tyr411His left the ER in cells grown at a permissive temperature (31 degrees C). Three novel (p.Asp486Tyr, p.Leu527Arg, c.1045-15 T > G) and two known mutations (p.Pro743Leu, p.Ala787Thr) of OCA2 were found in fourteen families. Exon-trapping assays with a construct containing a novel c.1045-15 T > G mutation revealed an error in splicing. No mutation in TYRP1, SLC45A2, and SLC24A5 was found in the remaining 16 families. Clinical evaluation of the families segregating either TYR or OCA2 mutations showed nystagmus, photophobia, and loss of pigmentation in the skin or hair follicles. Most of the affected individuals had grayish-blue colored eyes.Conclusions: Our results show that ten and fourteen families harbored mutations in the TYR and OCA2 genes, respectively. Our findings, along with the results of previous studies, indicate that the p.Cys35Arg, p.Arg278* and p.Gly419Arg alleles of TYR and the p.Asp486Tyr and c.1045-15 T > G alleles of OCA2 are the most common causes of OCA in Pakistani families. To the best of our knowledge, this study represents the first documentation of OCA2 alleles in the Pakistani population. A significant proportion of our cohort did not have mutations in known OCA genes. Overall, our study contributes to the development of genetic testing protocols and genetic counseling for OCA in Pakistani families.