PDF(Pubmed)
Abstract：
α-1,2-mannosyltransferase (ALG9) germline variants are linked to autosomal dominant polycystic kidney disease (ADPKD). Many individuals affected with ADPKD possess polycystic livers as a common extrarenal manifestation. We performed whole exome sequencing in a female with autosomal dominant polycystic liver disease (ADPLD) without kidney cysts and established the presence of a heterozygous missense variant (c.677G>C p.(Gly226Ala)) in ALG9. In silico pathogenicity prediction and 3D protein modeling determined this variant as pathogenic. Loss of heterozygosity is regularly seen in liver cyst walls. Immunohistochemistry indicated the absence of ALG9 in liver tissue from this patient. ALG9 expression was absent in cyst wall lining from ALG9- and PRKCSH-caused ADPLD patients but present in the liver cyst lining derived from an ADPKD patient with a PKD2 variant. Thus, heterozygous pathogenic variants in ALG9 are also associated with ADPLD. Somatic loss of heterozygosity of the ALG9 enzyme was seen in the ALG9 patient but also in ADPLD patients with a different genetic background. This expanded the phenotypic spectrum of ADPLD to ALG9.
摘要：
α-1,2-甘露糖基转移酶（ALG9）种系变体与常染色体显性多囊肾病（ADPKD）相关。许多患有ADPKD的个体具有多囊肝作为常见的肾外表现。我们在一个没有肾囊肿的常染色体显性遗传性多囊性肝病（ADPLD）女性中进行了全外显子组测序，并确定了ALG9中存在杂合错义变异（c.677G>Cp.（Gly226Ala））。计算机致病性预测和3D蛋白质建模确定该变体为致病性。在肝囊肿壁中经常出现杂合性丢失。免疫组织化学显示该患者的肝组织中不存在ALG9。ALG9表达在ALG9和PRKCSH引起的ADPLD患者的囊肿壁衬里中不存在，但存在于具有PKD2变体的ADPKD患者的肝囊肿衬里中。因此，ALG9中的杂合致病变异也与ADPLD相关。在ALG9患者以及具有不同遗传背景的ADPLD患者中都观察到ALG9酶杂合性的体细胞丢失。这将ADPLD的表型谱扩展到ALG9。
