Department of Human Genetics, McGill University, Montreal, Canada.
The Research Institute of the McGill University Health Centre, Montreal, Canada.
Eur J Hum Genet. 2024 Sep;32(9):1184-1189. doi: 10.1038/s41431-024-01668-x. Epub 2024 Jul 10.
Biallelic pathogenic variants in the gene CC2D2A cause a spectrum of ciliopathies, including Joubert and Meckel syndrome, which frequently involve the kidney; however, no cases of isolated renal disease (i.e., nephronophthisis) have yet been reported. In an adult with a clinical presentation consistent with nephronophthisis, next-generation sequencing identified a rare homozygous nonsense variant in CC2D2A (c.100 C > T; p.(Arg34*)). Tissue-specific expression data and promoter activity analysis demonstrates that this variant primarily affects a transcript isoform predominant in the kidneys but does not affect the transcript isoforms predominant in other tissues typically involved in CC2D2A-related ciliopathies (e.g., cerebellum, liver). Expression analysis of patient-specific cDNA in MDCK cells demonstrates partial translation re-initiation downstream of p.(Arg34*) as a possible escape mechanism from nonsense mediated decay. These data provide mechanistic insights in support of this novel genotype-phenotype association.
CC2D2A 基因中的双等位致病性变异导致了一系列纤毛病，包括 Joubert 和 Meckel 综合征，这些疾病常累及肾脏；然而，尚未有孤立性肾脏疾病（即肾单位肾痨病）的病例报道。在一位临床表现符合肾单位肾痨病的成年患者中，下一代测序鉴定出 CC2D2A 中一个罕见的纯合无义变异（c.100C>T；p.(Arg34*))。组织特异性表达数据和启动子活性分析表明，该变异主要影响肾脏中主要存在的一种转录本异构体，但不影响通常涉及 CC2D2A 相关纤毛病的其他组织中主要存在的转录本异构体（例如小脑、肝脏）。在 MDCK 细胞中对患者特异性 cDNA 的表达分析表明，p.(Arg34*)下游的部分翻译重新起始可能是一种无义介导的衰变的逃逸机制。这些数据提供了支持这种新型基因型-表型关联的机制见解。
