Isolated polycystic liver disease genes define effectors of polycystin-1 function
Isolated polycystic liver disease genes define effectors of polycystin-1 function
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DOI：
10.1172/jci90129
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发表时间：
2017-05-01
影响因子：
15.9
通讯作者：
Somlo, Stefan
中科院分区：
文献类型：
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作者：
Besse, Whitney;Dong, Ke;Somlo, Stefan
显性遗传性孤立性多囊肝(PCLD)是指在放射学和病理学上与常染色体显性遗传性多囊肾病相同的肝囊肿，但没有临床相关的肾囊肿。在PCLD指征病例中，已知致病基因的不到40%。在这里，我们使用完整的外显子组测序来发现102名不相关的患者，这些患者被排除在2个最常见的PCLD基因PRKCSH和SEC63的突变之外，以确定另外3个基因ALG8、GANAB和SEC61B的杂合功能丧失突变。与PRKCSH和SEC63类似，这些基因编码的蛋白质是内质网中蛋白质生物发生途径的组成部分。我们在细胞系模型中灭活了这些候选基因，以表明每个基因的功能丧失都会导致多囊蛋白-1的缺陷成熟和运输，多囊蛋白-1是囊性病变的中心决定因素。尽管作用途径相同，但每种PCLD基因产物对多囊蛋白-1的生物发生都有不同的影响。我们还在全基因组的基础上发现了常染色体隐性遗传性多囊肾病基因PKHD1杂合突变的丰富，表明成年PKHD1携带者可以出现临床上的PCLD。这些发现定义了多囊蛋白-1功能的遗传和生化调节因子，并提供了对人类主要多囊疾病谱的更完整的定义。
Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.