COL4A3、COL4A4和COL4A5基因变异相关的肾脏疾病及其致病机制

doi:10.12372/jcp.2026.25e1075

摘要/Abstract

摘要：

胶原Ⅳ是肾小球基底膜的核心结构蛋白，由COL4A3、COL4A4和COL4A5基因编码的α链组装形成α3α4α5三聚体，对维持肾小球基底膜的结构完整性和滤过功能至关重要。这3个基因变异可导致一系列遗传性肾脏疾病，其中Alport综合征是最典型的代表，临床以血尿、进行性肾功能减退、感音神经性耳聋和眼部异常为特征，遗传模式涵盖X连锁、常染色体隐性和常染色体显性。此外，COL4A3、COL4A4和COL4A5基因变异还与薄基底膜肾病（TBMN）、家族性IgA肾病、局灶节段性肾小球硬化（FSGS）、激素抵抗性肾病综合征（SRNS）以及不明原因的终末期肾病（ESRD）等多种肾脏疾病密切相关。近年来，随着高通量测序技术的广泛应用，基因检测在疾病诊断、预后评估和精准治疗中的价值日益凸显。本文系统综述了COL4A3至COL4A5基因相关肾脏疾病的临床表现、分子遗传机制及其临床管理策略，以期为该类疾病的早期诊断和个体化治疗提供理论依据和实践指导。

关键词: 胶原Ⅳ, Alport综合征, 基因检测, 慢性肾脏病

Abstract:

Collagen Ⅳ is the core structural protein of the glomerular basement membrane, composed of α chains encoded by the COL4A3, COL4A4, and COL4A5 genes, which assemble into the α3α4α5 trimer. It plays a crucial role in maintaining the structural integrity and filtration function of the glomerular basement membrane. Variations in these three genes can lead to a spectrum of inherited kidney diseases, with Alport syndrome being the most representative. Clinically, Alport syndrome is characterized by hematuria, progressive renal dysfunction, sensorineural hearing loss, and ocular abnormalities, with inheritance patterns including X-linked, autosomal recessive, and autosomal dominant. Additionally, variations in the COL4A3-COL4A5 genes are closely associated with various kidney diseases, such as thin basement membrane nephropathy (TBMN), familial IgA nephropathy, focal segmental glomerulosclerosis (FSGS), steroid-resistant nephrotic syndrome (SRNS), and end-stage renal disease (ESRD) of unknown etiology. In recent years, with the widespread application of high-throughput sequencing technologies, genetic testing has increasingly demonstrated its value in disease diagnosis, prognosis assessment, and precision medicine. This article systematically reviews the clinical manifestations, molecular genetic mechanisms, and clinical management strategies of COL4A3-COL4A5-related kidney diseases, aiming to provide a theoretical foundation and practical guidance for early diagnosis and individualized treatment of these conditions.

Key words: collagen Ⅳ, Alport syndrome, genetic testing, chronic kidney disease

中图分类号:

李浩淼, 张晓宇, 韩媛, 车若琛, 陈秋霞, 赵三龙, 丁桂霞. COL4A3、COL4A4和COL4A5基因变异相关的肾脏疾病及其致病机制[J]. 临床儿科杂志, 2026, 44(4): 362-372.

LI Haomiao, ZHANG Xiaoyu, HAN Yuan, CHE Ruochen, CHEN Qiuxia, ZHAO Sanlong, DING Guixia. Kidney diseases related to COL4A3, COL4A4 and COL4A5 gene variations and their pathogenic mechanisms[J]. Journal of Clinical Pediatrics, 2026, 44(4): 362-372.

图/表 1

表1

COL4A3~COL4A5基因变异相关的肾脏疾病表型总结"

COL4A3~COL4A5 基因变异相关肾脏疾病	致病基因	遗传模式	临床表现	进展至ESRD时间	文献
GBM相关肾脏疾病
AS
XLAS	COL4A5	XLD	男性患者病情最重，几乎全部在儿童期即出现镜下血尿和蛋白尿，并伴有高频感音神经性耳聋（32%~83%）和特征性眼部病变（如圆锥形晶状体，6%~35%）	绝大多数男性患者会在40岁前进展至ESRD，其进展速度与基因变异类型密切相关	[4,48]
XLAS	COL4A5	XLD	女性携带者临床表现多样且通常较轻，超过90%有血尿，约70%出现蛋白尿，但仅少数出现听力或眼部受累	15%~30%女性患者在60岁前进展为ESRD	[4,48]
ADAS	COL4A3/ COL4A4	AD	患者通常表现为镜下血尿（约90%）和蛋白尿（约70%），但肾外表现（听力损失<10%，眼部病变<5%）少见	整体病程进展缓慢，预后相对最好，仅约20%的患者有进展至ESRD的风险，中位年龄约为67岁	[4]
ARAS	COL4A3/ COL4A4	AR	患者临床表现严重，100%出现血尿和蛋白尿，约60%伴有听力损失和眼部病变	所有患者均会进展至ESRD，未治疗者进展至ESKD的中位年龄约为22.5岁，是进展最快的一种类型	[4]
双基因型AS	COL4A3, COL4A4	AD/AR	患者66%有蛋白尿，25 %有肾衰竭，27 %有听力损害，没有发现眼部异常	ESRD发生中位年龄约57岁，其严重度介于ADAS与ARAS之间	[13, 15-16]
	COL4A3/ COL4A4, COL4A5	－	男性患者92%有蛋白尿，33%出现肾功能异常，60%有听力损害，50%有视觉异常	ESRD发生时间主要由COL4A5基因变异本身的严重性主导
	COL4A3/ COL4A4, COL4A5	－	由于X染色体随机失活，女性患者表型较轻且变异性大；其中，62%有蛋白尿，8%有肾衰竭，15%有听力损害，7%有非特异性视觉异常，83%GBM分层，17%GBM变薄	相较于常染色体相关的AS，发生ESRD的风险增加且发病年龄提前
AS-DL	COL4A5, COL4A6	XLD	患者除表现出典型的AS特征（如血尿、进行性肾衰竭、高频感音神经性耳聋及眼部病变）外，还会在食管、气管支气管或女性生殖道早发DL，导致吞咽困难、呼吸困难或生殖道梗阻，且其严重程度在男、女性中相近	参考XLAS	[17]
TBMN	COL4A3/ COL4A4	AD	持续性或间歇性镜下血尿，常伴有GBM弥漫性变薄，但10%~30%可在中老年（通常≥50岁）出现蛋白尿、高血压或FSGS，并逐渐进展至ESRD	多数患者预后良好，多在50~70岁发展至ESRD	[11]
囊性肾病	COL4A3/ COL4A4/ COL4A5	XLD/ AD/ AR	肾囊肿更常见于40岁以后或已伴有蛋白尿、肾功能减退的成年患者，但在儿童病例中亦有报道。囊肿通常数量较少、增大缓慢，可单侧或双侧，不引起肾脏体积显著增大，并常与FSGS病变共存，提示存在严重的基底膜缺陷	肾功能预后主要取决于其AS的严重程度，即取决于不同的基因变异类型；ADAS中囊肿出现通常意味着ESRD风险显著增高	[28,49]
继发性损伤相关肾脏疾病
家族性IgAN	COL4A3/ COL4A4/ COL4A5	XLD/ AD/ AR	持续性血尿和肾病水平蛋白尿，肾脏病理兼具IgA沉积和GBM变薄的特征。此类患者对激素/免疫抑制剂治疗的反应差异较大	进展至ESRD的风险与基因变异类型密切相关	[35]
FSGS	COL4A3/ COL4A4/ COL4A5	XLD/ AD/ AR	早期出现肾病范围蛋白尿和血尿为突出表现的FSGS，其肾脏病理虽符合FSGS，但超微结构上缺乏典型的Alport样GBM分层改变	患者进展至ESRD的时间差异显著，从数年到数十年不等，其中复合杂合或纯合截断变异者往往起病早、进展快，而杂合错义变异者病程相对缓和	[45,50]

表1

参考文献 62

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