Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
Ophthalmology. 2011 Jul;118(7):1444-8. doi: 10.1016/j.ophtha.2010.10.047. Epub 2011 Feb 18.
To describe the mutations in the CLRN1 gene in patients from 2 consanguineous Pakistani families diagnosed with autosomal recessive retinitis pigmentosa (arRP).
Case-series study.
Affected and unaffected individuals of 2 consanguineous Pakistani families and 90 unaffected controls from the same population. Informed consent was obtained from participants and the protocol was approved by a local institutional review board.
Patients of 2 consanguineous families were genotyped with single-nucleotide polymorphism microarrays for genome-wide linkage analysis. The search for potential candidate genes within the 8-Mb overlapping homozygous region in these families revealed the presence of CLRN1, a gene previously known to cause Usher's syndrome type III (USH3), which was analyzed by direct sequence analysis. The clinical diagnosis was based on the presence of night blindness, fundoscopic findings, and electroretinography (ERG) results. Additionally, pure tone audiometry was performed to rule out Usher's syndrome.
Fundoscopy, single-nucleotide polymorphism microarray, DNA sequence analysis, ERG, and audiometry.
Sequencing of CLRN1 revealed novel missense mutations (p.Pro31Leu and p.Leu154Trp) segregating in 2 families. Analysis of fundus photographs indicated attenuation of the retinal vessels, and bone spicule pigmentation in the periphery of the retina. The ERG responses were indicative of a rod-cone pattern of the disease. Audiometric assessment revealed no hearing impairment, thereby excluding Usher's syndrome. Subcellular localization studies demonstrated the retention of the mutant proteins in the endoplasmic reticulum, whereas the wild-type protein was mainly present at the cell membrane.
The RP-associated mutations p.Pro31Leu and p.Leu154Trp may represent hypomorphic mutations, because the substituted amino acids located in the transmembrane domains remain polar, whereas more severe changes have been detected in patients with USH3. These data indicate that mutations in CLRN1 are associated not only with USH3, but also with nonsyndromic arRP.
描述在 2 个巴基斯坦近亲家系中被诊断为常染色体隐性视网膜色素变性（arRP）的患者中 CLRN1 基因突变。
病例系列研究。
2 个巴基斯坦近亲家系中的受影响和未受影响个体以及来自同一人群的 90 名未受影响对照者。获得了参与者的知情同意，该方案得到了当地机构审查委员会的批准。
对 2 个近亲家系的患者进行单核苷酸多态性微阵列基因组全连锁分析。在这些家系中，对 8 Mb 重叠纯合区域内的潜在候选基因进行搜索，发现了 CLRN1 的存在，CLRN1 是先前已知导致 III 型 Usher 综合征（USH3）的基因，对其进行直接序列分析。临床诊断基于夜盲、眼底检查和视网膜电图（ERG）结果。此外，进行纯音测听以排除 Usher 综合征。
眼底检查、单核苷酸多态性微阵列、DNA 序列分析、ERG 和测听。
CLRN1 测序发现了 2 个家系中存在新的错义突变（p.Pro31Leu 和 p.Leu154Trp）。眼底照片分析表明视网膜血管衰减，周边出现骨刺样色素沉着。ERG 反应提示疾病呈杆状-锥状模式。听力评估未发现听力损伤，从而排除了 Usher 综合征。亚细胞定位研究表明突变蛋白在内质网中滞留，而野生型蛋白主要存在于细胞膜上。
与 RP 相关的突变 p.Pro31Leu 和 p.Leu154Trp 可能代表功能减退突变，因为位于跨膜结构域的取代氨基酸仍然具有极性，而在 USH3 患者中检测到更严重的变化。这些数据表明，CLRN1 突变不仅与 USH3 相关，而且与非综合征性 arRP 相关。
