C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle

Floriot, Sandrine; Vesque, Christine; Rodriguez, Sabrina; Bourgain-Guglielmetti, Florence; Karaı̈skou, Anthi; Gautier, Mathieu; Duchesne, Amandine; Barbey, Sarah; Fritz, Sébastien; Vasilescu, Alexandre; Bertaud, Maud; Moudjou, Mohammed; Halliez, Sophie; Cormier‐Daire, Valérie; Hokayem, Joyce El; Nigg, Erich A.; Manciaux, Luc; Guatteo, Raphaël R.; Cesbron, Nora; Toutirais, Géraldine; Eggen, Andre A.; Schneider‐Maunoury, Sylvie; Boichard, Didier; Sobczak-Thépot, Joëlle; Schibler, Laurent

doi:10.1038/ncomms7894

Cited by 36 publications

(39 citation statements)

References 39 publications

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“…One of its major components is c-Nap1 (alias CEP250) (32), which serves as anchoring points for rootletin, Cep68 and LRCC45 that form the thin filaments of the linker (33, 34). Loss of function of each of these proteins leads to premature centriole splitting (32)(33)(34)(35). However, we showed that Ift52 did not colocalized with c-Nap1 ( Figure 5B) and immunostainings of c-Nap1, rootletin, Cep68 and LRCC45 did not reveal any obvious defects of localisation of these proteins to the centrosome in Ift52 -/cells compared to control cells ( Figure S3C-E).…”

Section: Ift52 -/Cells Exhibit Centriole Splittingmentioning

confidence: 87%

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

Dupont

Humbert

Huber

et al. 2019

Human Molecular Genetics

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Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.

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Section: Ift52 -/Cells Exhibit Centriole Splittingmentioning

confidence: 87%

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

Dupont

Humbert

Huber

et al. 2019

Human Molecular Genetics

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“…Mutations in the human homolog of C - Nap1 , called CEP250 or CEP2 , are associated with Usher syndrome, a disease characterized by retinitis pigmentosa and hearing loss [ 55 ]. In cattle, mutations in C - Nap1 are associated with microcephaly, suggesting that the linker between mother and daughter centrioles plays important roles in neural development in mammals [ 56 ].…”

Section: Murine Basal Body Structurementioning

confidence: 99%

A primer on the mouse basal body

García

Reiter

2016

Cilia

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The basal body is a highly organized structure essential for the formation of cilia. Basal bodies dock to a cellular membrane through their distal appendages (also known as transition fibers) and provide the foundation on which the microtubules of the ciliary axoneme are built. Consequently, basal body position and orientation dictates the position and orientation of its cilium. The heart of the basal body is the mother centriole, the older of the two centrioles inherited during mitosis and which is comprised of nine triplet microtubules arranged in a cylinder. Like all ciliated organisms, mice possess basal bodies, and studies of mouse basal body structure have made diverse important contributions to the understanding of how basal body structure impacts the function of cilia. The appendages and associated structures of mouse basal bodies can differ in their architecture from those of other organisms, and even between murine cell types. For example, basal bodies of immotile primary cilia are connected to daughter centrioles, whereas those of motile multiciliated cells are not. The last few years have seen the identification of many components of the basal body, and the mouse will continue to be an extremely valuable system for genetically defining their functions.

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“…Le gain de cette approche réside surtout dans la petite fraction à séquencer par rapport au génome total et donc au coût plus limité par échantillon, autorisant à travailler sur un nombre bien plus élevé d'échantillons. Cette technologie a été utilisée en 2010 pour la caractérisation de l'anomalie SHGC en race Montbéliarde (Floriot et al 2015). Elle a comme difficulté essentielle le temps et le travail nécessaires pour dessiner les oligonucléotides de capture, ainsi que le coût de leur synthèse qui ne se justifie que si le nombre d'échantillons à traiter est important.…”

Section: / Recherche De Mutations Candidates Par Séquençage Du Génomeunclassified

Du phénotype à la mutation causale : le cas des anomalies récessives bovines

et al. 2020

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Cet article présente la méthodologie utilisée pour identifier la mutation responsable d’une anomalie génétique à partir de cas d’animaux affectés. Dans un premier temps, une collection de cas aussi homogènes que possible est constituée, de la même race et avec les mêmes signes cliniques, complétée par une population témoin apparentée mais non atteinte. Une analyse de pedigree est possible pour rechercher l’ancêtre commun qui a pu transmettre l’anomalie à chacun des cas. Le génotypage par puce permet de mettre en évidence très rapidement une petite région du génome homozygote et identique à tous les marqueurs qui contient la mutation recherchée. La mutation est ensuite identifiée par séquençage du génome de quelques cas, filtrage des variants observés sur la base d’une part, de leur présence chez d’autres animaux, et d’autre part, de leur annotation fonctionnelle. Une validation statistique est ensuite pratiquée par génotypage à grande échelle, pour vérifier l’association totale entre génotype et phénotype. Enfin, la causalité de la mutation est étudiée par analyse fonctionnelle, incluant l’analyse des ARN et des protéines, l’imagerie cellulaire, voire la création de modèles transgéniques.

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C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle

Cited by 36 publications

References 39 publications

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

A primer on the mouse basal body

Du phénotype à la mutation causale : le cas des anomalies récessives bovines

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