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

Marie Alice Dupont; Camille Humbert; Céline Huber; Quentin Siour; Ida Chiara Guerrera; Vincent Jung; Anni Christensen; Aurore Pouliet; Meriem Garfa-Traore; Patrick Nitschké; Marie Injeyan; Kathryn Millar; David Chitayat; Patrick Shannon; Katta Mohan Girisha; Anju Shukla; Charlotte Mechler; Esben Lorentzen; Alexandre Benmerah; Valérie Cormier-Daire; Cécile Jeanpierre; Sophie Saunier; Marion Delous

doi:10.1093/hmg/ddz091

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

Marie Alice Dupont, Camille Humbert, Céline Huber, Quentin Siour, Ida Chiara Guerrera, Vincent Jung, Anni Christensen, Aurore Pouliet, Meriem Garfa-Traore, Patrick Nitschké, Marie Injeyan, Kathryn Millar, David Chitayat, Patrick Shannon, Katta Mohan Girisha, Anju Shukla, Charlotte Mechler, Esben Lorentzen, Alexandre Benmerah, Valérie Cormier-DaireCécile Jeanpierre, Sophie Saunier, Marion Delous

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Human Molecular Genetics
Volume	28
Issue	16
Pages (from-to)	2720-2737
Number of pages	18
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddz091
Publication status	Published - 15 Aug 2019
Externally published	Yes

Keywords

ALLELES
B CORE
CANDIDATE
CILIA
DEFECTS
ENCODES
GENES
INTRAFLAGELLAR TRANSPORT PROTEIN
NEPHRONOPHTHISIS
ZEBRAFISH

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10.1093/hmg/ddz091

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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

@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",

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",

}

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, vol. 28, no. 16, pp. 2720-2737. https://doi.org/10.1093/hmg/ddz091

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. / Dupont, Marie Alice; Humbert, Camille; Huber, Céline et al.
In: Human Molecular Genetics, Vol. 28, No. 16, 15.08.2019, p. 2720-2737.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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

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

SN - 0964-6906

VL - 28

SP - 2720

EP - 2737

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

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

Abstract

Keywords

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