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.

Graphical abstract

关键词

先天性肾脏和尿路畸形 / 前B细胞白血病转录因子1 / 转录调控 / 致病机制

Key words

congenital anomalies of the kidney and urinary tract / pre-B-cell leukemia transcription factor 1 / transcriptional regulation / pathogenic mechanism

先天性肾脏和尿路畸形（congenital anomalies of the kidney and urinary tract, CAKUT）是儿童常见的先天性疾病，主要临床表现为肾发育不良、泌尿道畸形等，是儿童终末期肾脏病的常见原因^[1]。CAKUT常伴有肾功能损害，首发症状隐匿，产前以肾脏发育异常和羊水过少为主，出生后以肾脏合并其他器官发育异常为主^[2]，严重者需要长期透析或肾移植治疗，对患儿家庭及社会造成较大负担^[3]。早期诊断并尽早治疗，可改善部分患者肾脏预后。CAKUT的致病因素涉及遗传、环境等多方面，其中遗传因素最为突出。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CAKUT的致病单基因^[4]，例如HNF1B基因突变会引起肾囊肿和肾发育不良等异常^[5]；PAX2基因突变可导致肾囊肿和肾-视神经缺损综合征^[6]等。

前B细胞白血病转录因子1（pre-B-cell leukemia transcription factor 1, PBX1）基因在胚胎发育早期即表达，主要定位于后肾间充质细胞，调控肾单位形成及肾脏血管网络发育，是肾脏胚胎发育不可或缺的调控因子。2017年首次出现PBX1基因突变可导致综合征型CAKUT的报道，证实了二者之间存在密切关联^[7]。基于目前已报道的患者种族分布，尚未发现PBX1基因突变相关CAKUT存在明显种族差异。由于PBX1在肾脏胚胎发育中的关键调控作用的相关系统性总结较少，突变型与临床表型的相关性尚不明确。因此，本文拟系统梳理PBX1基因的结构和PBX1蛋白的功能，探讨PBX1基因在肾脏发育过程中的作用机制，分析PBX1基因型-表型的相关性，为CAKUT精准诊疗提供理论参考。

1 PBX1基因及PBX1蛋白结构

PBX1基因定位于1号染色体长臂2区3带，编码由430个氨基酸组成的转录因子PBX1蛋白^[8]。PBX1蛋白属于三氨基酸环延伸（three amino acid loop extension, TALE）同源异型框蛋白家族，TALE蛋白家族包括哺乳动物的前B细胞白血病转录因子PBX1～4、嗜病毒整合因子MEIS和PBX调控蛋白PREP，主要参与胚胎发育过程中的生长和分化，并且在物种间高度保守^[9]。PBX1与其同源蛋白PBX2、PBX3、PBX4具有类似结构^[10]。不同的是，PBX蛋白家族的表达具有时空差异。PBX1基因主要在胚胎期表达，是肾脏胚胎发育所必需的调控因子，但在成人组织中低表达；此外，PBX1基因在多种癌症中的表达均异常上调^[11]；PBX2基因在胚胎神经发育中作用突出^[12]，且在胚胎造血及成人造血组织中表达，与白血病发生密切相关^[13]；PBX3基因在胶质瘤中高表达，且其表达水平随着肿瘤恶性程度的增加而升高^[14]；目前对PBX4基因研究较少，已知其在肠道发育和结直肠癌中可能起作用^[15]。

PBX1蛋白有两个核心功能域，分别是PBC结构域和同源结构域（homologous domain, HD）。PBC结构域位于氨基端，分为PBC-A和PBC-B两个亚域。PBC-A域包含核输出信号序列，可调控蛋白核质穿梭。PBC-B域包含5个丝氨酸磷酸化位点，可以通过翻译后修饰调节PBX1的转录活性。HD结构域位于羧基端，由60个氨基酸构成的“螺旋-转角-螺旋”结构组成，是PBX1与DNA结合的关键区域^[16]。PBX1中部含有核定位信号序列，介导PBX1蛋白进入细胞核，从而发挥转录调控功能。PBX1在胚胎发育早期即表达，主要表达于后肾间充质细胞^[17]。

2 PBX1基因变异是导致肾脏发育不良的胚胎基础

人类胚胎发育是一个复杂且精确的过程，经历3个重要阶段，分别是前肾、中肾和后肾，其中前肾在胚胎发育极早期发挥短暂作用，随后逐渐退化，中肾为后肾发育奠定基础，而后肾是发育为有功能肾脏的核心阶段。在人类妊娠约4.5周时（小鼠胚胎11.5 d），来自中胚层的中肾管形成输尿管芽，随后输尿管进入邻近的后肾间充质形成后肾。输尿管芽诱导部分间充质细胞凝聚在其末端形成帽状间充质干细胞，这部分细胞将经间充质-上皮转化形成肾小管，肾小管的延长和肾脏血管内皮逐渐形成肾单位。同时，输尿管芽与后肾间充质细胞的相互作用形成肾脏集合系统^[18]。如果调控上述过程的基因功能缺失则会造成先天性肾脏发育异常。

3 PBX1基因调节肾脏发育的机制

SCHNABEL等^[19]在胚胎小鼠中敲除PBX1基因，小鼠表现为肾脏体积缩小，30%的小鼠出现单侧肾缺如，并且多于胚胎发育第15天死亡，这证明PBX1基因是胚胎肾脏发育不可或缺的因子，敲除PBX1基因可导致肾脏缺如甚至胚胎死亡。PBX1基因在胚胎肾单位分化中同样具有重要作用，可通过调控RET、GDNF等基因表达，促进输尿管芽萌出及向肾单位的分化；在肾单位血管分化中，PBX1基因通过抑制血管壁细胞（vascular wall cells, VMCs）中PDGFRβ基因的过早表达，维持肾动脉树的正常形态发生，确保肾单位与血管网络的共同发育^[20]。在PBX1基因纯合缺失小鼠中，胚胎输尿管分支数量进行性减少，胚胎发育第14.5天时分支数仅为野生型的1/3^[19]。HURTADO等^[20]研究证实PBX1蛋白可结合PDGFRβ基因顺式调控元件并抑制其转录，进而调控VMCs分化动力学，维持肾脏动脉网络的正常层级构型；PBX1缺失会导致VMCs过早分化、肾脏血管构型异常及肾功能衰竭；而降低PDGFRβ剂量可挽救相关缺陷。

在输尿管芽萌出阶段，PBX1与MEIS1形成复合物，调控GDNF基因表达，GDNF与输尿管芽表面RET受体结合从而启动下游信号通路调控输尿管芽增殖与形成分支^[19]；在肾血管发育阶段，PBX1抑制VMCs中PDGFRβ过早表达，维持肾动脉正常形态发生。此外，PBX1还可通过其PBC结构域和HOXA7、HOXA10结合形成异源二聚体复合物，调控肾脏与尿路的发育^[21]。此外，最新单细胞测序研究显示，PBX1突变导致后肾间充质细胞中WNT/β-catenin信号通路关键基因（如WNT9B、LEF1）表达下调，从而引发肾发育不良^[22]。综上，PBX1基因是胚胎肾脏发育、肾单位形成及肾脏正常血管网络形成的重要调控因子。

4 PBX1基因突变的基因型-表型分析

随着分子遗传学技术的发展，全外显子测序可有效检测PBX1基因的各类变异，为CAKUT综合征的分子诊断提供了关键技术支撑，新突变位点和新表型正逐渐被发现。CAKUT综合征的临床表现具有异质性，以先天性肾脏发育不良为主，包括肾脏缺如和肾脏异位等，输尿管、膀胱、尿道畸形较为少见^[7]。目前，PBX1基因的致病性变异类型包括错义突变、无义突变、剪接突变等多种类型。目前已报道的PBX1致病性变异、临床表型及功能结构域分布见表1。

仅HD结构域存在致死性突变，PBC-A和PBC-B结构域无致死突变，以综合征型CAKUT为主（见图1）。PBX1致病性变异的基因型与临床表型的关联具有特异性（见图2）。PBC-A结构域突变患者外耳畸形发生率为57%，听力下降的发生率为28%，均高于PBC-B结构域及HD结构域。PBC-A结构域内7例突变均伴随明确肾脏异常，无一例外，表型包括肾小球巨大稀少症（Oligomeganephronia, OMN）、双肾发育不良、局灶节段性肾小球硬化（focal segmental glomerulosclerosis, FSGS）及系膜增生性肾小球肾炎（mesangial proliferative glomerulonephritis, MSPGN）等多种类型，且多数病例会合并外耳畸形、耳聋、眼距增宽、方颅等听力-面容异常，部分病例还累及心脏、生殖系统、骨骼及呼吸系统，其中c.319C>T突变患者因无脾症、肺发育不全、室间隔缺损等严重异常，最终死亡。

相较于PBC-A，PBC-B结构域突变的表型异质性更为突出。该结构域主要参与维持PBX1蛋白稳定性及与DNA结合能力，由图2可知，7例患者中5例表现为双侧肾发育不良/不全，肾功能损伤差异较大，而听力-面容异常的发生率明显降低，多系统异常也主要集中在神经发育迟缓、心脏畸形方面，无致死性病例报道。

HD结构域的突变表型较为严重，与PBC结构域突变以肾脏表型为核心不同，HD结构域突变中肾脏异常的发生比例较其他结构域低，取而代之的是明显的多系统畸形，如法洛四联症、完全性肺静脉异位引流、肺发育不全、先天性膈疝等，致死病例占比高达三成，且存活病例多伴随生长发育迟缓、肌张力低下、智力障碍等异常，反映出该结构域突变对全部器官发育的影响大于肾脏局部。

目前仅收集到1例非核心结构域突变（c.992C>A），表现为双肾发育不良，肾功能仅达慢性肾脏病2期，伴随轻度遗尿症状，无听力-面容异常及其他系统受累，表型轻微且局限，这一结果也表明了非核心结构域对PBX1核心功能影响有限。

5 PBX1基因突变表型差异性机制分析

PBC-A结构域是PBX1蛋白中高度保守的蛋白互作区域，其核心功能是与PREP/MEIS蛋白结合形成转录调控复合物^[39]。当PBC-A结构域突变时，复合物形成受阻，导致肾脏发育相关基因表达紊乱，进而引发多种肾脏异常^[40]。此外，PBX1基因可通过调控颅神经嵴细胞的增殖与分化参与颌面部骨骼、外耳等结构的发育^[41]，且与内耳毛细胞发育相关基因（如Hox家族）的表达调控密切相关^[42-43]。PBC-A结构域突变会破坏PBX1与MEIS1的相互作用，导致颅神经嵴细胞增殖分化异常，引发外耳畸形；同时内耳毛细胞发育相关基因表达紊乱，导致听力丧失。临床中若发现CAKUT合并耳部畸形，应优先考虑PBX1基因检测，这一表型组合可作为重要的分子诊断线索。此外，该结构域突变还会影响PBX1对心脏、生殖系统等器官发育相关基因的调控，导致多系统受累^[44]。

PBC-B结构域突变的听力-面容异常发生率显著低于PBC-A结构域，可能因为该区域对PBX1调控颅颌面及听觉器官发育相关基因的影响相对较弱^[41，45]。目前无致死性病例报道，可能因为该结构域突变未完全阻断PBX1的核心功能，仍能维持关键器官（如肺、脾脏）的基本发育需求^[46]。

HD结构域是PBX1直接结合DNA的关键结构域，其通过识别特定DNA序列调控靶基因转录，同时与Hox蛋白相互作用以增强转录调控特异性^[47-48]。HD结构域突变的致死病例占比高达三成且存活病例多有生长发育迟缓等异常。RUSCITTI等^[37]证实HD结构域突变会导致PBX1蛋白结合靶基因的能力下降，如c.868C>T变异导致DNA结合能力降低约90%，无法正常结合多器官发育相关靶基因的启动子区域，进而引发广泛的基因表达紊乱，这是该结构域突变表型严重且以多系统畸形为主的核心原因。

6 临床意义与未来展望

PBX1作为TALE蛋白家族转录因子，在胚胎肾脏发育中发挥核心作用，是肾脏发育调控网络的重要节点。PBX1基因变异的临床表现以肾发育不良为核心表型，常伴尿路畸形及神经、心脏等多系统的肾外表现。鉴于HD结构域突变的高致死率，对于产前超声提示双肾发育不良的胎儿，可将PBX1基因纳入优先筛查范围，以尽快明确遗传学病因，评估致死风险，并为妊娠决策、产后多学科干预提供科学依据。

尽管PBX1与CAKUT的关联已得到证实，但仍有诸多科学问题有待解决，未来研究可聚焦于大样本队列以完善表型谱、明确基因型-表型关联等。目前PBX1基因变异尚无特异性靶向治疗方法，临床多以对症治疗为主，未来可利用单细胞测序等技术解析PBX1调控网络并挖掘关键靶基因，探索基因治疗、小分子药物等干预策略，并借助肾脏类器官模型加速药物研发，深入研究翻译后修饰机制以挖掘新的干预靶点。

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基金资助

国家自然科学基金面上项目(82570813)