Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia
Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia
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DOI：
10.1016/j.ajhg.2016.05.028
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发表时间：
2016-07-07
影响因子：
9.8
通讯作者：
Loeys, Bart L.
中科院分区：
文献类型：
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作者：
Bolar, Nikhita Ajit;Golzio, Christelle;Loeys, Bart L.
常染色体显性肾小管间质性肾病（ADTKD）包括一组以肾小管和间质异常为特征的疾病，导致肾功能缓慢进行性丧失，需要透析和肾移植。 UMOD、MUC1 和 REN 突变是许多（但不是全部）ADTKD 病例的原因。我们报告了两个患有 ADTKD 和先天性贫血并伴有宫内生长迟缓或中性粒细胞减少症的家庭。超声和肾活检分别显示肾脏发育不良并伴有囊肿，肾小管萎缩并伴有继发性肾小球硬化。排除已知的 ADTKD 基因，结合连锁分析、全外显子组测序和靶向重测序，确定了 SEC61A1-c.553A>G (p.Thr185Ala) 和 c.200T > G (p.Val67Gly) 中的杂合错义变异，两者均影响 SEC61 中功能重要且保守的残基。两种瞬时表达的 SEC6A1A 变体都离域到高尔基体，这一发现在受影响个体的肾活检中得到证实。斑马鱼胚胎中 sec61al2 的抑制或 CRISPR 介导的删除会诱导前肾小管而非前肾管的卷积缺陷，这与在受影响个体中观察到的肾小管萎缩一致。编码这两种致病等位基因之一的人类 mRNA 未能挽救这种表型，而人类野生型 mRNA 则能完全挽救这种表型。总而言之，这些发现提供了一种机制，通过这种机制，SEC61A1 的突变会导致常染色体显性遗传的进行性慢性肾病综合征。我们强调跨内质网膜的蛋白质易位缺陷，这是 SEC61 复合物的主要作用，也是 ADTKD 的致病机制。
Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T > G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.