Mutations of CEP83 Cause Infantile Nephronophthisis and Intellectual Disability

Abstract

Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome

“…Because HLS is now known as a ciliopathy, we then combined a targeted capture strategy for candidate ciliary genes with next-generation sequencing, as described previously, by using DNA from fetus II:3. 6,7 In brief, ciliary exome-targeted sequencing and bioinformatics filtering were conducted with a Custom SureSelect Capture Kit (Agilent Technologies) targeting 4.5 Mb of 20,168 exons (1,221 ciliary candidate genes). Agilent SureSelect libraries were prepared from 3 mg of genomic DNA sheared with a Covaris S2 Ultrasonicator according to manufacturer's instructions.…”

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

“…Similarly, Sclt1 is a TF protein required for ciliary assembly (Tanos et al 2013). Mutations in two other TF genes, CEP164 and CEP83, can cause nephronophthisis (NPHP), a cystic kidney disease, sometimes accompanied by other signs such as intellectual disability (Chaki et al 2012; Failler et al 2014). Both proteins are required for ciliogenesis and Cep164 can also participate in the DNA damage response, a function it can share with other NPHP proteins (Graser et al 2007; Chaki et al 2012; Tanos et al 2013; Daly et al 2016).…”

The essential roles of transition fibers in the context of cilia

“…Mutations in CEP164 (also called NPHP15) and CEP83 (also called NPHP18) cause nephronophthisis-related ciliopathies (NPHP-RC) [68, 69]. SCLT1 is mutated in patients with orofaciodigital syndrome (OFD) type IX [70], and mutations in TTBK2 cause neurodegenerative disease spinocerebellar ataxia type 11 [37].…”