Ciliopathies with Skeletal Anomalies and Renal Insufficiency due to Mutations in the IFT-A Gene WDR19

Abstract

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.

Clinical and genetic characteristics of Japanese nephronophthisis patients

“…Even the most frequent of these extrarenal manifestations, pigmentary retinal degeneration, was present only in some patients and not in others, even among children showing the same NPHP1 deletion. Similar lesions also have been reported in Jeune, Joubert, oro-facial-digital (OFD1), and Meckel syndromes [13,18,19]. NPHP1 mRNA is expressed predominantly in a wide range of extrarenal tissues including pituitary gland, spine, testis, lymph nodes, and thyroid [14].…”

Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

“…Death occurred in 27.2% and 40%, respectively. The oldest patient was a 21-year-old woman with a WDR19 mutation who had a kidney transplant for end-stage renal disease [patient II-1, Bredrup et al, 2011]. Similarly in ATD-JS, death occurred in 44% of reported patients with the majority ($60%) aged <5 years.…”

“…Clinical manifestations of Sensenbrenner syndrome are highly variable and may differ between and within families [Gilissen et al, 2010;Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Bacino et al, 2012;Hoffer et al, 2013]. The phenotypes resulting from biallelic mutations in any one of the four known genes (i.e., IFT122, WDR35, IFT43, or WDR19) are not distinguishable [Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Bacino et al, 2012;Hoffer et al, 2013].…”

“…The phenotypes resulting from biallelic mutations in any one of the four known genes (i.e., IFT122, WDR35, IFT43, or WDR19) are not distinguishable [Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Bacino et al, 2012;Hoffer et al, 2013]. Reports published to date involve too few affected individuals to extract reliable insights into genotype-phenotype correlations.…”

“…Because of the skeletal and ectodermal anomalies, it has been referred to as cranioectodermal dysplasia (CED) [Gellis and Feingold, 1979;Savill et al, 1997;Tamai et al, 2002;Obikane et al, 2006;Fry et al, 2009;Konstantinidou et al, 2009], but for this study, we use the eponym Sensenbrenner syndrome. There is significant phenotypic variability and dramatic advances using microarray analysis and targeted-and whole-exome sequencing (WES) have demonstrated molecular heterogeneity [Gilissen et al, 2010;Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Hoffer et al, 2013], and showed that this syndrome is probably due to cilia dysfunction [Baker and Beales, 2009;Konstantinidou et al, 2009;Walczak-Sztulpa et al, 2010;Hildebrandt et al, 2011]. OMIM currently lists four molecular subtypes as CED1 (#218330, chr 3q221.3-q22.1, IFT122), CED2 (#613610, chr 2p24.1, WDR35), CED3 (#614099, chr 14q24.3, IFT43), and CED4 (#614378, chr 4p14, WDR19).…”