PDF(Pubmed)
Abstract：
Protein-truncating variants in α-1,3-glucosyltransferase (ALG8) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic ALG8 variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic ALG8 variant carriers, we performed targeted ALG8 screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in ALG8 were discovered in sixteen patients. The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of <5 renal cysts that do not affect renal function is common in this population. Three-dimensional homology modeling demonstrated that six variants cause a truncated ALG8 protein with abnormal functioning, and one variant is predicted to destabilize ALG8. For the seventh variant, immunostaining of the liver tissue showed a complete loss of ALG8 in the cystic cells. ALG8-associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype-phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.
摘要：
α-1,3-葡萄糖基转移酶（ALG8）中的蛋白质截短变体是轻度囊性肾病表型的危险因素。这些变体与肝囊肿之间的关联是有限的。我们的目标是在我们的常染色体显性遗传多囊性肝病（ADPLD）个体队列中鉴定致病性ALG8变异。为了精细绘制致病性ALG8变异携带者的表型谱，我们在478例ADPLD患者中进行了有针对性的ALG8筛查，以及来自两个大型ADPLD家族的48例单例和4例患者的外显子组测序。在16例患者中发现了8种新颖的和1种先前报道的ALG8致病变异。ALG8临床表型范围从轻度到重度多囊肝病，从无数小到多个大的肝囊肿。不影响肾功能的<5个肾囊肿的存在在该人群中是常见的。三维同源性建模表明，六个变异导致截短的ALG8蛋白功能异常，并且预测一个变体会破坏ALG8的稳定性。对于第七种变体，肝组织的免疫染色显示囊性细胞中ALG8的完全丧失。ALG8相关ADPLD具有广泛的临床谱，包括发展少量肾囊肿的可能性。这拓宽了ADPLD基因型-表型谱并缩小了肝脏特异性ADPLD和肾脏特异性ADPKD之间的差距。
