Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms

Abstract

Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies. Such grouping is underscored by two major observations: the fact that genes encoding ciliary proteins can contribute causal and modifying mutations across several clinically discrete ciliopathies, and the emerging realization that an understanding of the clinical pathology of one ciliopathy can provide valuable insight into the pathomechanism of renal cyst formation elsewhere in the ciliopathy spectrum. In this review, we discuss and attempt to stratify the different lines of proposed cilia-driven mechanisms for cystogenesis, ranging from mechano- and chemo-sensation, to cell shape and polarization, to the transduction of a variety of signaling cascades. We evaluate both common trends and differences across the models and discuss how each proposed mechanism can contribute to the development of novel therapeutic paradigms.

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

“…In syndromic forms of PKD, the mutated proteins are proposed to regulate ciliary protein trafficking and, hence, influence ciliogenesis; therefore, structural ciliary abnormalities, including length defects, have been associated with these diseases (8)(9)(10). However, in PKD1, the majority of studies have not detected cilia length defects, but the data are not conclusive, as these studies were largely conducted by light microscopy using cultured cells (14,15,80,81).…”

“…For example, cyst development has been strongly associated with defects to the primary cilia, as evident from model systems and syndromic PKD forms, categorizing PKD as a ciliopathy (8,9). Structural and functional cilia defects, including length abnormalities, have been characterized in several types of PKD, including the infantile onset autosomal recessive form (ARPKD, MIM no.…”

“…Structural and functional cilia defects, including length abnormalities, have been characterized in several types of PKD, including the infantile onset autosomal recessive form (ARPKD, MIM no. 263200) (8)(9)(10)(11)(12). However, no clear ciliary structural abnormalities have been described in PKD1 (13)(14)(15).…”

Clinical and ultrasonographical characterization of childhood cystic kidney diseases in Egypt

“…3 Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies that are characterized by a wide spectrum of phenotypes, including polycystic kidney, hepatic disease, malformations in the central nervous system, skeletal defects, retinal degeneration, and obesity. 4,5 To date, ciliary disruption has been linked to many human genetic kidney disorders, such as autosomal dominant and recessive polycystic kidney disease (ADPKD and ARPKD), tuberous sclerosis (TSC), medullary cystic kidney disease (MCKD), nephronophthisis (NPHP) and related disorders including Joubert syndrome (JBTS). 6,7 Cystic renal dysplasia and other renal phenotypes have also been associated with ciliary dysfunction, mostly within the context of syndromes that affect early development, such as the Meckel-Gruber syndrome (MKS), and the shortrib-polydactyly syndrome.…”

“…These genes encode various subsets of ciliary proteins including: nephrocystins, BardetBiedl syndrome (BBS) proteins BBSome, nephrocystins and JBTS/MKS proteins, interflagellar transport complexes (IFT A & B); as well as fibrocystin, polycystins, Hamartin (TSC1), Tuberin (TSC2), and uromodulin among others. 4,9 Mutations in at least 13 different genes have been associated with the enormously genetically heterogeneous NPHP, nevertheless 70% of patients still remain genetically unexplained. Next generation sequencing (NGS) methods, mostly used for research purposes, are accelerating the process of identifying novel disease genes and gaining more insights into genotype-phenotype correlations in a time and cost effective effort.…”