Ciliopathies

Abstract

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease. Mutations in the same gene can give rise to diverse phenotypes depending on the mutated allele. At the same time, there is broad phenotypic overlap between different monogenic genes. The identification of monogenic causes of ciliopathies has furthered the understanding of molecular mechanism and cellular pathways involved in the pathogenesis.

Figure 1.

Monogenic genes of nephronophthisis-related ciliopathies (NPHP-RC) cause distinct but widely overlapping phenotypes. Monogenic genes of NPHP-RC are categorized into four major phenotypes, namely, JBTS (blue, Joubert syndrome [JBTS]: congenital brain malformations, cerebellar vermis hypoplasia, and intellectual disability), NPHP/SLS (red, nephronophthisis/Senior–Loken syndrome [SLS]: nephronophthisis [NPHP], retinal degeneration, coloboma), BBS (yellow, Bardet–Biedl syndrome [BBS]: obesity, intellectual disability, retinal degeneration, cystic kidney disease, polydactyly, hypogonadisms), and skeletal ciliopathies (green, oral-facial-digital syndrome [OFD], cranioectodermal dysplasia (CED), short-rib thoracic dysplasia [SRTD]). As shown in a Venn diagram, numerous genes can give rise to overlapping phenotypes if mutated. Meckel–Gruber syndrome (MKS), the most severe clinical manifestation of NPHP-RC, can be caused by mutations in 10 monogenic genes. With the exception of the genes B9D1 and B9D2 that have not been described in association with other phenotypes, MKS is caused by mutations in monogenic genes of nephronophthisis, Joubert syndrome, and Bardet–Biedl syndrome on an allelic basis. White text indicates genes in which liver involvement has been reported.

Figure 2.

Subcellular localization of proteins encoded by monogenic genes of nephronophthisis-related ciliopathies (NPHP-RC). Subcellular localization of proteins encoded by monogenic genes of NPHP-RC is depicted. Proteins are color-coded based on their respective disease group as shown in Table 1 (red/orange/pink: nephronophthisis [NPHP], Senior–Loken syndrome [SLS], Joubert syndrome [JBTS], Meckel–Gruber syndrome [MKS]; yellow: Bardet–Biedl syndrome [BBS]; green: skeletal ciliopathies). It becomes apparent that disease groups cluster to distinct subcellular localizations. IFT, Intraflagellar transport.