Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome.
Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome.
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DOI：
10.1038/s41598-022-06525-9
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发表时间：
2022-02-17
影响因子：
4.6
通讯作者：
Savige J
中科院分区：
文献类型：
--
作者：
Gibson JT;Huang M;Shenelli Croos Dabrera M;Shukla K;Rothe H;Hilbert P;Deltas C;Storey H;Lipska-Ziętkiewicz BS;Chan MMY;Sadeghi-Alavijeh O;Gale DP;Genomics England Research Consortium;Cerkauskaite A;Savige J
Alport综合征是最常见的遗传性肾脏疾病，导致Alport综合征的COL4A3-COL4A5基因中近一半的致病性变体导致Gly置换。本研究检测了决定临床特征严重程度的Gly置换的分子特征。在Leiden开放变异数据库中，X连锁Alport综合征男性患者中影响Gly的致病性COL4A5变异体与肾衰竭（n = 157）和听力损失诊断（n = 80）时的年龄相关。在英国100，000基因组计划中，常染色体显性遗传Alport综合征患者中影响Gly的杂合致病性COL4A3和COL4A4变异体（n = 304）与血尿风险相关。Gly置换按外显子位置（1至20或21至羧基末端）、与非胶原区域相邻（中断或末端）以及置换残基引起的不稳定程度分层。致病性COL4A5变体导致Gly替换为高度不稳定的残基，使肾衰竭的中位年龄降低7岁（p = 0.002），听力损失诊断的年龄降低21岁（p = 0.004）。邻近非胶原区域的替代延迟了19年的肾衰竭（p = 0.014）。杂合致病性COL4A3和COL4A4变异体导致Gly被高度不稳定残基（Arg、瓦尔、Glu、Asp、Trp）取代，与血尿风险增加相关（p = 0.018），而与非胶原区域相邻的变异体与血尿风险降低相关（p = 0.046）。外显子位置没有影响。此外，在gnomAD的正常人群中，与非胶原区域相邻的COL4A5变体过度表达（p <0.001）。在X连锁和常染色体显性遗传Alport综合征中，取代和附近残基的性质决定了Gly取代引起血尿、早发性肾衰竭和听力损失的风险。
Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3–COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.
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影响因子：
56.9
作者：
BELLA, J;EATON, M;BERMAN, HM
通讯作者：
BERMAN, HM
影响因子：
3.9
作者：
Houdayer, Claude;Caux-Moncoutier, Virginie;Stoppa-Lyonnet, Dominique
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影响因子：
13.6
作者：
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作者：
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TRYGGVASON, K