PBX1基因突变在先天性肾脏与尿路畸形中的研究进展

Research progress of PBX1 gene mutations in congenital anomalies of the kidney and urinary tract

摘要:

先天性肾脏和尿路畸形（CAKUT）是导致儿童终末期肾脏病的重要原因，遗传因素在CAKUT的发病机制中具有重要作用。CAKUT根据有无肾外累及可分为综合征型与非综合征型，目前已发现50多种单基因突变可导致综合征型CAKUT的发生。前B细胞白血病转录因子1（PBX1）是三氨基酸环延伸同源异型框蛋白家族转录因子成员，可与HOX、MEIS等蛋白结合形成复合物，对胚胎发育尤其是肾脏和尿路的发育起重要的调节作用。近年来，随着全外显子测序、基因芯片等分子诊断技术的普及，PBX1基因突变被发现可导致综合征型CAKUT。由于该基因突变罕见，目前对PBX1基因的功能、基因型-表型的总结较少，因此该文探讨了PBX1基因突变导致先天性肾脏发育畸形的机制，总结PBX1基因突变型和表型的关系。经分析发现，HD结构域突变致死率高达30%，以多系统严重畸形为主要表型；PBC结构域突变表型以综合征型CAKUT为主。这为CAKUT的个体化诊断、遗传咨询和未来潜在治疗提供理论基础。

Abstract:

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of end-stage renal disease in children, and genetic factors play a significant role in the pathogenesis of CAKUT. CAKUT can be classified into syndromic and non-syndromic types depending on whether there is extrarenal involvement. Mutations in more than 50 single genes have been identified to cause syndromic CAKUT. Pre-B-cell leukemia transcription factor 1 (PBX1) is a member of the three-amino-acid loop extension (TALE) homeodomain transcription factor family and can form complexes with proteins such as HOX and MEIS, playing an important regulatory role in embryonic development, especially in the development of the kidneys and urinary tract. In recent years, with the popularization of molecular diagnostic technologies such as whole-exome sequencing and gene chips, mutations in the PBX1 gene have been found to cause syndromic CAKUT. Since these gene mutations are rare, there is currently limited information on PBX1 gene function and genotype-phenotype correlations. Therefore, we explore the mechanisms by which PBX1 gene mutations lead to congenital kidney malformations and summarize the correlations between PBX1 gene mutations and phenotypes. Analysis shows that mutations in the HD domain have a mortality rate as high as 30%, mainly presenting as severe multisystem malformations, while mutations in the PBC domain primarily present as syndromic CAKUT. This provides a theoretical basis for personalized diagnosis, genetic counseling, and potential future therapies for CAKUT.