A novel mutation c.29G>A in the X-linked GPR143 gene causes ocular albinism type 1 in a family
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摘要: 对一个眼白化病1型(OA1)家系进行致病基因突变筛查与分析。该家系患者均表现出典型OA1临床特征，如先天性双眼视力发育不良、眼球震颤、斜视以及虹膜、眼底色素减少伴黄斑中心凹发育不全。采用全外显子组测序技术对先证者进行筛查，发现X染色体上GPR143基因存在c.29G>A(p.Cys10Tyr)半合突变(第29位鸟嘌呤突变为腺嘌呤，导致编码的第10位半胱氨酸变为酪氨酸)。Sanger测序验证该突变存在于所有患病家系成员中。生物信息学分析显示，该突变导致GPR143蛋白质一级结构的分子量、等电点及不稳定指数升高，二级结构中α螺旋和延伸链比例增加，无规卷曲比例减少。利用PROVEAN、SIFT、Mutation Taster和Polyphen-2多种在线工具均预测该突变为致病性变异。本研究发现并确认了GPR143基因的一个新致病突变c.29G>A，拓展了该基因的突变谱，并从蛋白质构象角度为理解GPR143蛋白的功能提供了新见解。Abstract: This study conducted pathogenic gene mutation screening and analysis in a pedigree with ocular albinism type 1 (OA1). Affected individuals within the pedigree exhibited typical OA1 clinical features, including congenital bilateral visual impairment, nystagmus, strabismus, reduced iris and fundus pigmentation, and foveal hypoplasia. Whole-exome sequencing (WES) was performed on the proband, revealing a hemizygous mutation c.29G>A (p.Cys10Tyr) in the GPR143 gene located on the X chromosome. This mutation involves a guanine (G) to adenine (A) substitution at nucleotide position 29, resulting in the amino acid change cysteine (Cys) to tyrosine (Tyr) at position 10 of the encoded protein. Sanger sequencing confirmed the presence of this mutation in all affected family members. Bioinformatics analysis indicated that this mutation leads to alterations in the primary structure of the GPR143 protein, including increased molecular weight, isoelectric point (pI), and instability index. Changes in the secondary structure were also predicted, showing an increase in the proportion of alpha-helices and extended strands, accompanied by a decrease in the proportion of random coils. Multiple online prediction tools (PROVEAN, SIFT, Mutation Taster, and Polyphen-2) consistently classified this mutation as pathogenic. This study identified and confirmed a novel pathogenic mutation, GPR143 c.29G>A, broadening the mutational spectrum of this gene. Furthermore, it provides new insights into the functional implications of the GPR143 protein from a protein conformational perspective.
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Key words:
- Ocular albinism type 1 /
- GPR143 Gene /
- Sequencing /
- Mutation /
- Inheritance
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图 1 X连锁遗传性眼白化病1型患者家系图
注：Ⅰ为第一代，Ⅱ为第二代，Ⅲ为第三代。
Figure 1. Pedigree of a family with X-linked ocular albinism type Ⅰ
图 2 Ⅲ：1双眼欧堡眼底彩照
注：双眼视网膜部分色素脱失呈豹纹状，黄斑中心凹反光未见。A为右眼；B为左眼。
Figure 2. Optos color fundus photographs of proband Ⅲ: 1
图 3 双眼黄斑OCT检查结果
注：双眼均未见明显黄斑中心凹样结构。A为患者右眼，B为患者左眼，C为患者舅舅右眼，D为患者舅舅左眼。
Figure 3. Optical coherence tomography (OCT) findings of the macular region
图 4 该家系基因测序分析结果
注：患者X染色体GPR143基因存在一个半合子突变c.29G>A: p.Cys10Tyr(红色箭头所示)；患者母亲携带杂合突变c.29G>A；患者父亲GPR143基因c.29位点为正常序列。
Figure 4. Results of gene sequencing analysis in the family
表 1 GPR143c.29G>A: p.Cys10Tyr突变前后蛋白质构象对比分析
Table 1. Comparative analysis of protein conformation before and after the GPR143 c.29G>A: p.Cys10Tyr mutation
结构 特性 正常 GPR143c.29G>A: p.Cys10Tyr 一级结构 氨基酸数目 404 404 质量分数 43 878.19 43 938.22 等电点 7.53 7.54 不稳定指数 49.58 50.38 二级结构 α螺旋 40.84% 44.80% 延伸链 9.16% 9.41% 无规卷曲 50.00% 45.79% 
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表 2 预测GPR143突变(c.29G>A: p.Cys10Tyr)的致病性结果
Table 2. Pathogenicity prediction results for the GPR143 c.29G>A (p.Cys10Tyr) mutation
项目 PROVEAN SIFT Mutation Taster Polyphen-2 评分 -7.300 0.000 0.999 1.000 预测结果 有害的 有害的 致病的 可能是有害的
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