Insights into Autosomal Dominant Polycystic Kidney Disease from Genetic Studies
Insights into Autosomal Dominant Polycystic Kidney Disease from Genetic Studies
复制标题
从遗传学研究中对常染色体显性遗传性多囊肾病的认识
DOI：
10.2215/cjn.02320220
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发表时间：
2021-05-08
影响因子：
9.8
通讯作者：
Pei, York
中科院分区：
文献类型：
--
作者：
Lanktree, Matthew B.;Haghighi, Amirreza;Pei, York
常染色体显性多囊肾病是ESKD最常见的单基因病因。从患者和动物模型的遗传研究告知疾病病理生物学和强烈支持？阈值模型？其中囊肿形成是由单个肾小管上皮细胞内功能性多囊蛋白剂量降低到临界阈值以下触发的，这是由于（1）种系和体细胞PKD 1和/或PKD 2突变，（2）基因突变（例如，SEC 63、SEC 61 B、GANAB、PRKCSH、DNAJB 11、ALG 8和ALG 9），或（3）体细胞嵌合。遗传检测有可能为囊性肾病提供诊断和预后信息。然而，PKD 1的突变筛选是具有挑战性的，由于其大的尺寸和复杂性，使其既昂贵又劳动密集。此外，传统的桑格测序？基于遗传学的检测目前在阐明非典型多囊肾疾病的原因方面受到限制，例如家族内疾病不一致、非典型肾脏成像模式以及总肾脏体积和eGFR下降率之间的不一致疾病严重程度。此外，环境因素、遗传修饰剂和体细胞嵌合体也有助于疾病变异性，进一步限制了个体患者中突变类型的确定。下一代测序的最新创新有望以合理的成本改变和扩展分子诊断。通过对多发性囊性疾病和修饰基因的全面筛查，靶向基因组、全外显子组或全基因组测序有望提高诊断和预后准确性，以推进常染色体显性多囊肾病的个性化治疗。
Autosomal dominant polycystic kidney disease is the most common monogenic cause of ESKD. Genetic studies from patients and animal models have informed disease pathobiology and strongly support a ?threshold model? in which cyst formation is triggered by reduced functional polycystin dosage below a critical threshold within individual tubular epithelial cells due to (1) germline and somatic PKD1 and/or PKD2 mutations, (2) mutations of genes (e.g., SEC63, SEC61B, GANAB, PRKCSH, DNAJB11, ALG8, and ALG9) in the endoplasmic reticulum protein biosynthetic pathway, or (3) somatic mosaicism. Genetic testing has the potential to provide diagnostic and prognostic information in cystic kidney disease. However, mutation screening of PKD1 is challenging due to its large size and complexity, making it both costly and labor intensive. Moreover, conventional Sanger sequencing?based genetic testing is currently limited in elucidating the causes of atypical polycystic kidney disease, such as within-family disease discordance, atypical kidney imaging patterns, and discordant disease severity between total kidney volume and rate of eGFR decline. In addition, environmental factors, genetic modifiers, and somatic mosaicism also contribute to disease variability, further limiting prognostication by mutation class in individual patients. Recent innovations in next-generation sequencing are poised to transform and extend molecular diagnostics at reasonable costs. By comprehensive screening of multiple cystic disease and modifier genes, targeted gene panel, whole-exome, or whole-genome sequencing is expected to improve both diagnostic and prognostic accuracy to advance personalized medicine in autosomal dominant polycystic kidney disease.