Malaichamy Sivasankar, Sen Parveen, Sachidanandam Ramya, Arokiasamy Tharigopala, Lancelot Marie Elise, Audo Isabelle, Zeitz Christina, Soumittra Nagasamy
SNONGC department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
Department of Vitreo-Retinal Services, Medical Research Foundation, Chennai, India.
Mol Vis. 2014 Mar 21;20:341-51. eCollection 2014.
Congenital stationary night blindness (CSNB) is a non-progressive retinal disorder that shows genetic and clinical heterogeneity. CSNB is inherited as an autosomal recessive, autosomal dominant, or X-linked recessive trait and shows a good genotype-phenotype correlation. Clinically, CSNB is classified as the Riggs type and the Schubert-Bornschein type. The latter form is further sub-classified into complete and incomplete forms based on specific waveforms on the electroretinogram (ERG). There are no molecular genetic data for CSNB in the Indian population. Therefore, we present for the first time molecular profiling of eight families with complete CSNB (cCSNB).
The index patients and their other affected family members were comprehensively evaluated for the phenotype, including complete ophthalmic evaluation, ERG, fundus autofluorescence, optical coherence tomography, and color vision test. The known gene defects for cCSNB, LRIT3, TRPM1, GRM6, GPR179, and NYX, were screened by PCR direct sequencing. Bioinformatic analyses were performed using SIFT and PolyPhen for the identified missense mutations.
All eight affected index patients and affected family members were identified as having cCSNB based on their ERG waveforms. Mutations in the TRPM1 gene were identified in six index patients. The two remaining index patients each carried a GPR179 and GRM6 mutation. Seven of the patients revealed homozygous mutations, while one patient showed a compound heterozygous mutation. Six of the eight mutations identified are novel.
This is the first report on molecular profiling of candidate genes in CSNB in an Indian cohort. As shown for other cohorts, TRPM1 seems to be a major gene defect in patients with cCSNB in India.
先天性静止性夜盲（CSNB）是一种非进行性视网膜疾病，具有遗传和临床异质性。CSNB以常染色体隐性、常染色体显性或X连锁隐性性状遗传，表现出良好的基因型-表型相关性。临床上，CSNB分为里格斯型和舒伯特-博恩施泰因型。后一种类型根据视网膜电图（ERG）上的特定波形进一步细分为完全型和不完全型。印度人群中尚无CSNB的分子遗传学数据。因此，我们首次展示了8个完全性CSNB（cCSNB）家系的分子图谱。
对索引患者及其其他受影响的家庭成员进行全面的表型评估，包括完整的眼科评估、ERG、眼底自发荧光、光学相干断层扫描和色觉测试。通过PCR直接测序筛查cCSNB的已知基因缺陷LRIT3、TRPM1、GRM6、GPR179和NYX。使用SIFT和PolyPhen对鉴定出的错义突变进行生物信息学分析。
根据ERG波形，所有8名受影响的索引患者和受影响的家庭成员均被确定为患有cCSNB。在6名索引患者中鉴定出TRPM1基因突变。其余2名索引患者分别携带GPR179和GRM6突变。7名患者显示纯合突变，1名患者显示复合杂合突变。鉴定出的8个突变中有6个是新的。
这是关于印度队列中CSNB候选基因分子图谱的首次报告。正如其他队列所示，TRPM1似乎是印度cCSNB患者的主要基因缺陷。
