Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum

Cavalcanti, Denise Pontes; Huber, Céline; Sang, Kim-Hanh Le Quan; Baujat, Geneviève; Collins, Felicity; Delezoide, Anne‐Lise; Dagoneau, Nathalie; Merrer, Martine Le; Martinovic, Jéléna; Mello, Marcos Fernando S; Vekemans, Michel; Münnich, Arnold; Cormier‐Daire, Valérie

doi:10.1136/jmg.2009.069468

Cited by 66 publications

(62 citation statements)

References 28 publications

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“…Mutations in the gene encoding the IFT-A cytoplasmic dynein-2 motor heavy chain, DYNC2H1 (MIM 603297), are the most common cause of both SRPS and ATD 4, 5 . Recently, mutations in several additional genes have been shown to cause SRPS: IFT80 6, 7 (MIM 611263), WDR35 8, 9 (MIM 614091), WDR19 10 (MIM 614376), NEK1 11, 12 (MIM 263520), WDR34 13, 14 (MIM 615633), IFT140 15, 16 (MIM 266920), IFT172 17 (MIM 615630), WDR60 18 (MIM 615462), and TTC21B 19 (MIM 612014). Among the proteins encoded by the SRPS genes, WDR60 and WDR34 are intermediate chains of the DYNC2H1 cytoplasmic dynein-2 complex, highlighting its importance in skeletal development 20 .…”

Section: Introductionmentioning

confidence: 99%

Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome

et al. 2015

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The short rib polydactyly syndromes (SRPS) are a heterogeneous group of autosomal recessive, perinatal-lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs, and poly-dactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify additional SRPS genes and further unravel the functional basis for IFT. We perform whole exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable-length, including hyperelongated, cilia, Hedgehog pathway impairment, and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation, and skeletogenesis.

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Section: Introductionmentioning

confidence: 99%

Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome

et al. 2015

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“…The other three IFT-A members, IFT122 , IFT43 and WDR35 , are mutated in Sensenbrenner syndrome 20–22. Similarly, IFT144 and IFT80 are also mutated in overlapping milder syndromes and in more severe type III short-rib polydactyly 8 23 . IFT140 mutations were recently described in Mainzer-Saldino syndrome patients, and a subset of JATD patients with early end stage renal disease and frequent retinopathy 9 12.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing identifiesDYNC2H1mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

et al. 2013

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BackgroundJeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.Aims and methodsTo determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.Results and conclusionsWe detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

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“…Furthermore, cilia contain distinct complements of signaling machinery depending on the specific cell types on which they are found, suggesting that not all cilia are created equal in their signaling capabilities (Berbari et al, 2009). Although human ciliopathy patients offer excellent opportunities to study primary cilia functions, these patients are relatively rare and only a few of the mutations involve bona fide IFT genes (Arts et al, 2011; Cavalcanti et al, 2011). Thus, most insights into the molecular functions of cilia and IFT proteins in humans have been derived from comparative phenotypic analyses of genetic models across diverse systems.…”

Section: Introductionmentioning

confidence: 99%

Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation

Berbari

Kin

Sharma

et al. 2011

Developmental Biology

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Tumor necrosis factor alpha receptor 3 interacting protein 1 (Traf3ip1), also known as MIPT3, was initially characterized through its interactions with tubulin, actin, TNFR-associated factor-3 (Traf3), IL-13R1, and DISC1. It functions as an inhibitor of IL-13-mediated phosphorylation of Stat6 and in sequestration of Traf3 and DISC1 to the cytoskeleton. Studies of the Traf3ip1 homologs in C. elegans (DYF-11), Zebrafish (elipsa), and Chlamydomonas (IFT54) revealed that the protein localizes to the cilium and is required for ciliogenesis. Similar localization data has now been reported for mammalian Traf3ip1. This raises the possibility that Traf3ip1 has an evolutionarily conserved role in mammalian ciliogenesis in addition to its previously indicated functions. To evaluate this possibility, a Traf3ip1 mutant mouse line was generated. Traf3ip1mutant cells are unable to form cilia. Homozygous Traf3ip1 mutant mice are not viable and have both neural developmental defects and polydactyly, phenotypes typical of mouse mutants with ciliary assembly defects. Furthermore, in Traf3ip1 mutants the hedgehog pathway is disrupted, as evidenced by abnormal dorsal-ventral neural tube patterning and diminished expression of a hedgehog reporter. Analysis of the canonical Wnt pathway indicates that it was largely unaffected; however, specific domains in the pharyngeal arches have elevated levels of reporter activity. Interestingly, Traf3ip1 mutant embryos and cells failed to show alterations in IL-13 signaling, one of the pathways associated with its initial discovery. Novel phenotypes observed in Traf3ip1 mutant cells include elevated cytosolic levels of acetylated microtubules and a marked increase in cell size in culture. The enlarged Traf3ip1 mutant cell size was associated with elevated basal mTor pathway activity. Taken together, these data demonstrate that Traf3ip1 function is highly conserved in ciliogenesis and is important for proper regulation of a number of essential developmental and cellular pathways. The Traf3ip1 mutant mouse and cell lines will provide valuable resources to assess cilia function in mammalian development and also serve as a tool to explore the potential connections between cilia and cytoskeletal dynamics, mTor regulation, and cell volume control.

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Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum

Abstract: The findings show that mutations in IFT80 can also be responsible for a lethal form of SRP and provide the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum.

Cited by 66 publications

References 28 publications

Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome

Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome

Exome sequencing identifiesDYNC2H1mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation

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