Central Laboratory, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha, 410000, China.
School of Medicine, Changsha Medical University, Changsha, 410219, China.
BMC Med Genomics. 2023 Jan 18;16(1):9. doi: 10.1186/s12920-023-01430-0.
Retinitis pigmentosa (RP) is the most common type of inherited retinopathy. At least 69 genes for RP have been identified. A significant proportion of RP, however, remains genetically unsolved. In this study, the genetic basis of a Chinese consanguineous family with presumed autosomal recessive retinitis pigmentosa (arRP) was investigated.
Overall ophthalmic examinations, including funduscopy, decimal best-corrected visual acuity, axial length and electroretinography (ERG) were performed for the family. Genomic DNA from peripheral blood of the proband was subjected to whole exome sequencing. In silico predictions, structural modelling, and minigene assays were conducted to evaluate the pathogenicity of the variant.
A novel homozygous variant (NM_003320.4: c.1379A > G) in the TUB gene was identified as a candidate pathogenic variant in this parental consanguineous pedigree. This variant co-segregated with the disease in this pedigree and was absent in 118 ethnically matched healthy controls. It's an extremely rare variant that is neither deposited in population databases (1000 Genomes, ExAC, GnomAD, or Exome Variant Server) nor reported in the literature. Phylogenetic analysis indicated that the Asn residue at codon 460 of TUB is highly conserved across diverse species from tropicalis to humans. It was also completely conserved among the TUB, TULP1, TULP2, and TULP3 family proteins. Multiple bioinformatic algorithms predicted that this variant was deleterious.
A novel missense variant in TUB was identified, which was probably the pathogenic basis for arRP in this consanguineous family. This is the first report of a homozygous missense variant in TUB for RP.
色素性视网膜炎（RP）是最常见的遗传性视网膜病变。至少已经确定了 69 个 RP 基因。然而，相当一部分 RP 的遗传原因仍未得到解决。在这项研究中，我们调查了一个中国近亲家庭中假定的常染色体隐性色素性视网膜炎（arRP）的遗传基础。
对该家庭进行了全面的眼科检查，包括眼底检查、十进制最佳矫正视力、眼轴长度和视网膜电图（ERG）。对先证者外周血的基因组 DNA 进行了全外显子组测序。进行了计算机预测、结构建模和微基因检测，以评估该变体的致病性。
在这个父母近亲家系中，我们在 TUB 基因中发现了一个新的纯合变异（NM_003320.4：c.1379A>G），该变异被认为是候选致病变异。该变体在该家系中与疾病共分离，并且在 118 名种族匹配的健康对照中不存在。它是一种非常罕见的变体，既未在人群数据库（1000 基因组、ExAC、GnomAD 或 Exome Variant Server）中存储，也未在文献中报道。系统发育分析表明，TUB 中密码子 460 处的天冬酰胺残基在从热带到人类的各种物种中高度保守。它在 TUB、TULP1、TULP2 和 TULP3 家族蛋白中也是完全保守的。多种生物信息学算法预测该变体具有致病变异。
在 TUB 中发现了一个新的错义变异，这可能是这个近亲家庭中 arRP 的致病基础。这是 TUB 中 RP 同源错义变异的首例报道。
