<i>NEK1</i>and<i>DYNC2H1</i>are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases

Hokayem, Joyce El; Huber, Céline; Couvé, Adeline; Aziza, Jacqueline; Baujat, Geneviève; Bouvier, Raymonde; Cavalcanti, Denise Pontes; Collins, Felicity; Cordier, Marie‐Pierre; Delezoide, Anne‐Lise; Gonzalès, Marie; Johnson, Diana; Merrer, Martine Le; Levy‐Mozziconacci, Annie; Loget, Philippe; Martin‐Coignard, Dominique; Martinovic, Jéléna; Mortier, Geert; Perez, Marie-José; Roume, J.; Scarano, Gioacchino; Münnich, Arnold; Cormier‐Daire, Valérie

doi:10.1136/jmedgenet-2011-100717

Cited by 60 publications

(68 citation statements)

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“…These features are reminiscent of the spectrum of SRPII and SRPIV. 1,18,19 Thus, fetuses and individuals reported in this study all display lethal phenotypes consistent with a hedgehogsignaling defect and similar to the phenotype described Mutant Cells (A) KIAA0586 mutant fibroblasts from subject II:2 in family 2 showed an altered response to smoothened agonist (SAG; sc-202814, Santa Cruz; 5 mM for 18 hr), given that they induced less GLI1 and PTCH1 expression than did control cells. Primers used for real-time qRT-PCR are listed in Table S2.…”

supporting

confidence: 60%

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

Alby

Piquand

Huber

et al. 2015

The American Journal of Human Genetics

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KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.

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confidence: 60%

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

Alby

Piquand

Huber

et al. 2015

The American Journal of Human Genetics

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“…4F) and were also able to exclude cd28 (supplementary material Table S3D). Because mutations in DYNC2H1 cause thoracic dysplasia and ciliary defects in humans (Dagoneau et al, 2009;Merrill et al, 2009;El Hokayem et al, 2012;Schmidts et al, 2013) we first confirmed the nonsense mutation by sequencing single WT and homozygous aa65.6 pd1086 mutant larvae (Fig. 4G).…”

Section: Research Reportmentioning

confidence: 88%

Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish

et al. 2013

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SUMMARYForward genetic approaches in zebrafish have provided invaluable information about developmental processes. However, the relative difficulty of mapping and isolating mutations has limited the number of new genetic screens. Recent improvements in the annotation of the zebrafish genome coupled to a reduction in sequencing costs prompted the development of whole genome and RNA sequencing approaches for gene discovery. Here we describe a whole exome sequencing (WES) approach that allows rapid and costeffective identification of mutations. We used our WES methodology to isolate four mutations that cause kidney cysts; we identified novel alleles in two ciliary genes as well as two novel mutants. The WES approach described here does not require specialized infrastructure or training and is therefore widely accessible. This methodology should thus help facilitate genetic screens and expedite the identification of mutants that can inform basic biological processes and the causality of genetic disorders in humans.

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“…The two novel mutations p.A384V and p.Q1451X occur within the highly conserved DHC_N1 and DHC_N2 domains, respectively, which is considered to be the motile element of the dynein heavy chain, directing its movement along the dynein microtubules. Mutations occurring within this region have also been reported to csuse ATD [9,20]. Previous studies suggest that defective DYNC2H1 gene results in disruption of the Hedgehog signaling pathway, affecting the proliferation and differentiation of chondrogenic and osteogenic cells, and finally leads to chondrodysplasia phenotypes [21,22].…”

Section: Discussionmentioning

confidence: 99%

Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

Mei

Huang

Pan

et al. 2015

Clinica Chimica Acta

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NEK1andDYNC2H1are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases

Abstract: This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.

Cited by 60 publications

References 10 publications

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

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

Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish

Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

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