Mutations in human homologue of chickentalpid3gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes

Abstract

Background In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings. Methods In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients. Results We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune–Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function. Conclusions Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.

Biallelic mutations in mitochondrial tryptophanyl‐tRNA synthetase cause Levodopa‐responsive infantile‐onset Parkinsonism

“…A culture of dermal fibroblasts from the patient was established as previously described . Control fibroblasts were purchased from Coriell Institute for Medical Research.…”

“…A culture of dermal fibroblasts from the patient was established as previously described. 18 Control fibroblasts were purchased from Coriell Institute for Medical Research. For quantification of WARS2 and oxidative phosphorylation in dermal fibroblasts, human fibroblasts were trypsinized, pelleted, and resuspended in cell lysis buffer as previously described, 19 3 | RESULTS…”

Ciliopathies

“…Mutant zebrafish exhibit a characteristic ciliopathy phenotype including body axis curvature and pronephic renal cysts (Duldulao et al 2009). Furthermore, a canine model of NPHP (Finco et al 1970; Finco 1976; Finco et al 1977) and a chicken with a mutation of Talpid3 (Izpisua-Belmonte et al 1992; Davey et al 2006), the orthologue of the human Joubert gene KIAA0586 (Alby et al 2015; Bachmann-Gagescu et al 2015; Malicdan et al 2015; Roosing et al 2015), have been described.…”

A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C‐methyltransferase deficiency

“…Fibroblasts from III.6 were grown as explants from skin biopsies in 10% FBS in DMEM (Malicdan et al., ). Control fibroblasts were purchased from ATCC.…”

“…Fibroblasts from III.6 were grown as explants from skin biopsies in 10% FBS in DMEM (Malicdan et al, 2015). with the comparative CT method as described (Livak & Schmittgen, 2001 Nuclear and cytosolic fractions were prepared using the rapid, efficient, and practical (REAP) method (Suzuki, Bose, Leong-Quong, Fujita, & Riabowol, 2010).…”