Barroso-Gil Miguel, Olinger Eric, Sayer John A
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle Upon Tyne NE1 3BZ, U.K.
The Newcastle upon Tyne Hospitals NHS Foundation Trust, Renal Services, Freeman Road, Newcastle Upon Tyne NE7 7DN, U.K.
Biochem Soc Trans. 2021 Jun 30;49(3):1205-1220. doi: 10.1042/BST20200791.
Renal ciliopathies are a heterogenous group of inherited disorders leading to an array of phenotypes that include cystic kidney disease and renal interstitial fibrosis leading to progressive chronic kidney disease and end-stage kidney disease. The renal tubules are lined with epithelial cells that possess primary cilia that project into the lumen and act as sensory and signalling organelles. Mutations in genes encoding ciliary proteins involved in the structure and function of primary cilia cause ciliopathy syndromes and affect many organ systems including the kidney. Recognised disease phenotypes associated with primary ciliopathies that have a strong renal component include autosomal dominant and recessive polycystic kidney disease and their various mimics, including atypical polycystic kidney disease and nephronophthisis. The molecular investigation of inherited renal ciliopathies often allows a precise diagnosis to be reached where renal histology and other investigations have been unhelpful and can help in determining kidney prognosis. With increasing molecular insights, it is now apparent that renal ciliopathies form a continuum of clinical phenotypes with disease entities that have been classically described as dominant or recessive at both extremes of the spectrum. Gene-dosage effects, hypomorphic alleles, modifier genes and digenic inheritance further contribute to the genetic complexity of these disorders. This review will focus on recent molecular genetic advances in the renal ciliopathy field with a focus on cystic kidney disease phenotypes and the genotypes that lead to them. We discuss recent novel insights into underlying disease mechanisms of renal ciliopathies that might be amenable to therapeutic intervention.
肾纤毛病是一组异质性遗传性疾病,可导致一系列表型,包括囊性肾病和肾间质纤维化,进而发展为进行性慢性肾脏病和终末期肾病。肾小管由上皮细胞排列而成,这些上皮细胞具有伸入管腔的初级纤毛,初级纤毛充当感觉和信号细胞器。编码参与初级纤毛结构和功能的纤毛蛋白的基因突变会导致纤毛病综合征,并影响包括肾脏在内的许多器官系统。与具有强烈肾脏成分的原发性纤毛病相关的公认疾病表型包括常染色体显性和隐性多囊肾病及其各种类似疾病,包括非典型多囊肾病和肾单位肾痨。对遗传性肾纤毛病的分子研究通常能够在肾脏组织学和其他检查无济于事的情况下做出准确诊断,并有助于确定肾脏预后。随着分子认识的不断增加,现在很明显,肾纤毛病形成了一系列临床表型的连续体,其疾病实体在谱系的两个极端被经典地描述为显性或隐性。基因剂量效应、亚效等位基因、修饰基因和双基因遗传进一步增加了这些疾病的遗传复杂性。本综述将重点关注肾纤毛病领域最近的分子遗传学进展,重点是囊性肾病表型及其相关的基因型。我们讨论了最近对肾纤毛病潜在疾病机制的新见解,这些见解可能适合进行治疗干预。