Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy

Tuz, Karina; Bachmann‐Gagescu, Ruxandra; O’Day, Diana R.; Hua, Kiet; Isabella, Christine R.; Phelps, Ian G.; Stolarski, Allan; O’Roak, Brian J.; Dempsey, Jennifer C.; Lourenço, Charles Marques; Alswaid, Abdulrahman; Bönnemann, Carsten G.; Medne, Līvija; Nampoothiri, Sheela; Stark, Zornitza; Leventer, Richard J.; Topçu, Meral; Cansu, Ali; Jagadeesh, Sujatha; Done, Stephen; Ishak, Gisele E.; Glass, Ian A.; Shendure, Jay; Neuhauss, Stephan C.F.; Haldeman-Englert, Chad R.; Doherty, Dan

doi:10.1016/j.ajhg.2013.11.019

Cited by 105 publications

(116 citation statements)

References 32 publications

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“…While the percentage of ciliated cells was modest but significantly lower for TCTEX1D2 mutant fibroblasts compared with controls (Fig. 4e), no significant difference in ciliary length was observed after 24-h serum starvation, in contrast to the cilia shortening reported in individuals with mutations in other JATD/SRPS genes1219 (Fig. 4f).…”

Section: Resultsmentioning

confidence: 75%

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Schmidts¹,

Hou²,

Cortés³

et al. 2015

Nat Commun

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The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

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Section: Resultsmentioning

confidence: 75%

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Schmidts¹,

Hou²,

Cortés³

et al. 2015

Nat Commun

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“…The chicken talpid 3 mutant displayed a small chest and developed extremely short limbs with increased number of digits, many of which were morphologically identical 1. In human beings, mutations in CSPP1, a spindle pole-associated protein like KIAA0586, involved in the centrosome, were recently identified in patients with Joubert syndrome with features of Jeune syndrome 24 25. Finally, the product of CEP120 , mutated in some patients with Jeune syndrome,23 interacts with KIAA0586 26.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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.

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“…In three unrelated Brazilian families, the same combination of two CSPP1 RDVs was identified, suggesting that they might in fact be related. 20 None of the other recurring RDVs appeared to be associated with specific ethnic groups, so they may represent mutation hotspots (such as CEP290 G1890* identified in 10 unrelated families from 3 continents).…”

Section: Multiple Additional Clinical Featuresmentioning

confidence: 99%

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

et al. 2015

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Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion (CADD) algorithm with an optimized score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a “pure JS” phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS-subtypes. Conclusion This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes, and enable gene-specific treatments in the future.

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Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy

Cited by 105 publications

References 32 publications

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

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

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

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