Barua Moumita, Paterson Andrew D
Division of Nephrology, Toronto General Hospital, 200 Elizabeth Street, 8NU-855, Toronto, ON, M5G 2C4, Canada.
Department of Medicine, University of Toronto, Toronto, Canada.
Pediatr Nephrol. 2022 Feb;37(2):253-262. doi: 10.1007/s00467-021-04934-y. Epub 2021 Feb 26.
Specific variants in genes that encode the α3α4α5 chains of type IV collagen cause Alport syndrome (AS), which encompass a clinical spectrum from isolated hematuria to multisystem disease affecting sight, hearing and kidney function. The commonest form is X-linked Alport syndrome (XLAS; COL4A5) with autosomal AS (COL4A3 and COL4A4) comprising a minority of cases. While historic data estimates the frequency of AS at 1:5000-10,000, recent population-based genetic studies suggest the prevalence is considerably higher. Genome-wide association studies (GWAS) have been performed in the Icelandic (deCODE) and UK (UK Biobank) populations, demonstrating an association of type IV collagen gene variants with AS relevant kidney traits. In the Icelandic population, 1 in 600 carries a 2.5-kb COL4A3 coding deletion or a COL4A3 missense variant (rs200287952[A], Gly695Arg), both of which are strongly associated with hematuria and albuminuria (P values = 1.9 × 10 to 2.5 × 10). In the UK Biobank, COL4A4 rs35138315 (Ser969X; carrier frequency 0.13%) is strongly associated with both hematuria and albuminuria (P = 1.5 × 10). Thus, the frequency for autosomal AS is 5-16 times higher than the historic prevalence of all forms of the disorder. Furthermore, COL4A4 rs3518315 (Ser969X) is also a reported founder mutation in families with autosomal dominant focal and segmental glomerulosclerosis and autosomal recessive forms of AS. This supports an additive mode of inheritance for specific variants, wherein a number of copies of a mutation influence disease severity in a cumulative fashion. These studies did not include the X chromosome, excluding analysis of COL4A5, which represents an area for future study.
编码IV型胶原α3α4α5链的基因中的特定变异会导致奥尔波特综合征（AS），该病临床表现范围广泛，从孤立性血尿到影响视力、听力和肾功能的多系统疾病。最常见的形式是X连锁奥尔波特综合征（XLAS；COL4A5），常染色体AS（COL4A3和COL4A4）占少数病例。虽然历史数据估计AS的发病率为1:5000 - 10,000，但最近基于人群的基因研究表明其患病率要高得多。全基因组关联研究（GWAS）已在冰岛（deCODE）和英国（英国生物银行）人群中进行，证明IV型胶原基因变异与AS相关的肾脏特征有关。在冰岛人群中，600人中有1人携带一个2.5 kb的COL4A3编码缺失或一个COL4A3错义变异（rs200287952[A]，Gly695Arg），这两者都与血尿和蛋白尿密切相关（P值 = 1.9×10至2.5×10）。在英国生物银行中，COL4A4 rs35138315（Ser969X；携带频率0.13%）与血尿和蛋白尿都密切相关（P = 1.5×10）。因此，常染色体AS的频率比该疾病所有形式的历史患病率高5 - 16倍。此外，COL4A4 rs3518315（Ser969X）也是常染色体显性局灶节段性肾小球硬化和常染色体隐性AS家族中报道的奠基者突变。这支持了特定变异的累加遗传模式，即突变的多个拷贝以累积方式影响疾病严重程度。这些研究未包括X染色体，排除了对COL4A5的分析，这是未来研究领域。
