Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Orphanet J Rare Dis. 2012 Jun 26;7:44. doi: 10.1186/1750-1172-7-44.
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.
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.
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°C, but a significant fraction of p.Cys35Arg and p.Tyr411His left the ER in cells grown at a permissive temperature (31°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.
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.
眼皮肤白化病（OCA）是由一组遗传异质性的基因缺陷引起的，导致眼睛、皮肤和头发的色素丧失。TYR、OCA2、TYRP1 和 SLC45A2 基因突变已被证明可导致孤立性 OCA。目前还没有全面的分析来研究在巴基斯坦白化病人群中流行的 OCA 等位基因谱。
我们招募了 40 个大型巴基斯坦家庭，并对其进行了 OCA 基因和候选基因 SLC24A5 的筛查。使用计算机预测算法和人黑素细胞的体外研究评估蛋白功能效应。通过外显子捕获试验确定剪接位点突变的影响。
TYR 基因筛查显示在十个家庭中发现了四个已知（p.Arg299His、p.Pro406Leu、p.Gly419Arg、p.Arg278*）和三个新突变（p.Pro21Leu、p.Cys35Arg、p.Tyr411His）。体外研究表明，在 37°C 时，一种带有 EGFP 标记的突变（p.Pro21Leu、p.Cys35Arg 或 p.Tyr411His）酪氨酸酶在 ER 中被保留，但在 31°C 下培养的细胞中，p.Cys35Arg 和 p.Tyr411His 的相当一部分离开 ER。在十四个家庭中发现了三个新的（p.Asp486Tyr、p.Leu527Arg、c.1045-15T>G）和两个已知的（p.Pro743Leu、p.Ala787Thr）OCA2 突变。在剩余的 16 个家庭中未发现 TYRP1、SLC45A2 和 SLC24A5 的突变。对携带 TYR 或 OCA2 突变的家庭进行临床评估显示有眼球震颤、畏光和皮肤或毛囊色素丧失。大多数受影响的个体眼睛呈蓝灰色。
我们的结果表明，十个和十四个家庭分别携带 TYR 和 OCA2 基因的突变。我们的发现以及以前的研究结果表明，TYR 的 p.Cys35Arg、p.Arg278* 和 p.Gly419Arg 等位基因和 OCA2 的 p.Asp486Tyr 和 c.1045-15T>G 等位基因是巴基斯坦家庭 OCA 的最常见原因。据我们所知，这是首次在巴基斯坦人群中记录 OCA2 等位基因。我们队列中的很大一部分没有已知 OCA 基因的突变。总的来说，我们的研究为巴基斯坦家庭的 OCA 遗传检测方案和遗传咨询的制定做出了贡献。
