Liu Yan, Sheng Wenchao, Wu Jinying, Zheng Jie, Zhi Xiufang, Zhang Shuyue, Gu Chunyu, Guo Detong, Wang Wenhong
Department of Nephrology, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.
Graduate College of Tianjin Medical University, Tianjin Medical University, Tianjin, China.
Front Pediatr. 2022 Aug 17;10:890147. doi: 10.3389/fped.2022.890147. eCollection 2022.
Proximal renal tubular acidosis (pRTA) with ocular abnormalities is an autosomal recessive disease caused by variants in the Solute Carrier Family 4 Member 4 () gene. Patients present with metabolic acidosis and low plasma bicarbonate concentration (3∼17 mmol/L). In addition, they are often accompanied by ocular abnormalities, intellectual disability, and growth retardation. The patient underwent whole exome sequencing (WES) and bioinformatics analysis of variant pathogenicity in this study. Then, a minigene assay was conducted to analyze the splicing site variant further. Compound heterozygous variants in the gene (NM_003759.3), c.145C > T (p.Arg49*) and c.1499 + 1G > A, were detected by WES. The minigene assay showed an mRNA splicing aberration caused by the c.1499 + 1G > A variant. Compared with the wild type, the mutant type caused 4-base insertion between exons 10 and 11 of after expression in HEK293 cells. In conclusion, the c.1499 + 1G > A variant in the gene may be one of the genetic causes in the patient. Moreover, our study provides the foundation for future gene therapy of such pathogenic variants.
伴有眼部异常的近端肾小管酸中毒（pRTA）是一种常染色体隐性疾病，由溶质载体家族4成员4（）基因的变异引起。患者表现为代谢性酸中毒和低血浆碳酸氢盐浓度（3至17毫摩尔/升）。此外，他们常伴有眼部异常、智力残疾和生长发育迟缓。本研究中对该患者进行了全外显子组测序（WES）和变异致病性的生物信息学分析。然后，进行了小基因检测以进一步分析剪接位点变异。通过WES检测到基因（NM_003759.3）中的复合杂合变异，即c.145C>T（p.Arg49*）和c.1499+1G>A。小基因检测显示c.1499+1G>A变异导致mRNA剪接异常。与野生型相比，突变型在HEK293细胞中表达后导致基因第10和11外显子之间插入4个碱基。总之，基因中的c.1499+1G>A变异可能是该患者的遗传病因之一。此外，我们的研究为未来针对此类致病变异的基因治疗提供了基础。
