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

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Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. / Dupont, Marie Alice; Humbert, Camille; Huber, Céline; Siour, Quentin; Guerrera, Ida Chiara; Jung, Vincent; Christensen, Anni; Pouliet, Aurore; Garfa-Traore, Meriem; Nitschké, Patrick; Injeyan, Marie; Millar, Kathryn; Chitayat, David; Shannon, Patrick; Girisha, Katta Mohan; Shukla, Anju; Mechler, Charlotte; Lorentzen, Esben; Benmerah, Alexandre; Cormier-Daire, Valérie; Jeanpierre, Cécile; Saunier, Sophie; Delous, Marion.

I: Human Molecular Genetics, Bind 28, Nr. 16, 15.08.2019, s. 2720-2737.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Dupont, MA, Humbert, C, Huber, C, Siour, Q, Guerrera, IC, Jung, V, Christensen, A, Pouliet, A, Garfa-Traore, M, Nitschké, P, Injeyan, M, Millar, K, Chitayat, D, Shannon, P, Girisha, KM, Shukla, A, Mechler, C, Lorentzen, E, Benmerah, A, Cormier-Daire, V, Jeanpierre, C, Saunier, S & Delous, M 2019, 'Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion', Human Molecular Genetics, bind 28, nr. 16, s. 2720-2737. https://doi.org/10.1093/hmg/ddz091

APA

Dupont, M. A., Humbert, C., Huber, C., Siour, Q., Guerrera, I. C., Jung, V., Christensen, A., Pouliet, A., Garfa-Traore, M., Nitschké, P., Injeyan, M., Millar, K., Chitayat, D., Shannon, P., Girisha, K. M., Shukla, A., Mechler, C., Lorentzen, E., Benmerah, A., ... Delous, M. (2019). Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. Human Molecular Genetics, 28(16), 2720-2737. https://doi.org/10.1093/hmg/ddz091

CBE

Dupont MA, Humbert C, Huber C, Siour Q, Guerrera IC, Jung V, Christensen A, Pouliet A, Garfa-Traore M, Nitschké P, Injeyan M, Millar K, Chitayat D, Shannon P, Girisha KM, Shukla A, Mechler C, Lorentzen E, Benmerah A, Cormier-Daire V, Jeanpierre C, Saunier S, Delous M. 2019. Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. Human Molecular Genetics. 28(16):2720-2737. https://doi.org/10.1093/hmg/ddz091

MLA

Vancouver

Dupont MA, Humbert C, Huber C, Siour Q, Guerrera IC, Jung V o.a. Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. Human Molecular Genetics. 2019 aug 15;28(16):2720-2737. https://doi.org/10.1093/hmg/ddz091

Author

Dupont, Marie Alice ; Humbert, Camille ; Huber, Céline ; Siour, Quentin ; Guerrera, Ida Chiara ; Jung, Vincent ; Christensen, Anni ; Pouliet, Aurore ; Garfa-Traore, Meriem ; Nitschké, Patrick ; Injeyan, Marie ; Millar, Kathryn ; Chitayat, David ; Shannon, Patrick ; Girisha, Katta Mohan ; Shukla, Anju ; Mechler, Charlotte ; Lorentzen, Esben ; Benmerah, Alexandre ; Cormier-Daire, Valérie ; Jeanpierre, Cécile ; Saunier, Sophie ; Delous, Marion. / Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. I: Human Molecular Genetics. 2019 ; Bind 28, Nr. 16. s. 2720-2737.

Bibtex

@article{32627c4e38ad4106a3ddcd42e811908b,
title = "Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion",
abstract = "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) 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-localised 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 amongst IFT52-related cases and revealed a novel, extra-ciliary role for IFT52 which disruption may contribute to pathophysiological mechanisms.",
keywords = "ALLELES, B CORE, CANDIDATE, CILIA, DEFECTS, ENCODES, GENES, INTRAFLAGELLAR TRANSPORT PROTEIN, NEPHRONOPHTHISIS, ZEBRAFISH",
author = "Dupont, {Marie Alice} and Camille Humbert and C{\'e}line Huber and Quentin Siour and Guerrera, {Ida Chiara} and Vincent Jung and Anni Christensen and Aurore Pouliet and Meriem Garfa-Traore and Patrick Nitschk{\'e} and Marie Injeyan and Kathryn Millar and David Chitayat and Patrick Shannon and Girisha, {Katta Mohan} and Anju Shukla and Charlotte Mechler and Esben Lorentzen and Alexandre Benmerah and Val{\'e}rie Cormier-Daire and C{\'e}cile Jeanpierre and Sophie Saunier and Marion Delous",
note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2019",
month = aug,
day = "15",
doi = "10.1093/hmg/ddz091",
language = "English",
volume = "28",
pages = "2720--2737",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "16",

}

RIS

TY - JOUR

T1 - Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

AU - Dupont, Marie Alice

AU - Humbert, Camille

AU - Huber, Céline

AU - Siour, Quentin

AU - Guerrera, Ida Chiara

AU - Jung, Vincent

AU - Christensen, Anni

AU - Pouliet, Aurore

AU - Garfa-Traore, Meriem

AU - Nitschké, Patrick

AU - Injeyan, Marie

AU - Millar, Kathryn

AU - Chitayat, David

AU - Shannon, Patrick

AU - Girisha, Katta Mohan

AU - Shukla, Anju

AU - Mechler, Charlotte

AU - Lorentzen, Esben

AU - Benmerah, Alexandre

AU - Cormier-Daire, Valérie

AU - Jeanpierre, Cécile

AU - Saunier, Sophie

AU - Delous, Marion

N1 - © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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) 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-localised 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 amongst IFT52-related cases and revealed a novel, extra-ciliary role for IFT52 which disruption may contribute to pathophysiological mechanisms.

AB - 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) 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-localised 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 amongst IFT52-related cases and revealed a novel, extra-ciliary role for IFT52 which disruption may contribute to pathophysiological mechanisms.

KW - ALLELES

KW - B CORE

KW - CANDIDATE

KW - CILIA

KW - DEFECTS

KW - ENCODES

KW - GENES

KW - INTRAFLAGELLAR TRANSPORT PROTEIN

KW - NEPHRONOPHTHISIS

KW - ZEBRAFISH

U2 - 10.1093/hmg/ddz091

DO - 10.1093/hmg/ddz091

M3 - Journal article

C2 - 31042281

VL - 28

SP - 2720

EP - 2737

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

ER -