KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes

Audrey Putoux, Sophie Thomas, Karlien L.M. Coene, Erica E. Davis, Yasemin Alanay, Gönöl Ogur, Elif Uz, Daniela Buzas, Céline Gomes, Sophie Patrier, Christopher L. Bennett, Nadia Elkhartoufi, Marie Hélène Saint Frison, Luc Rigonnot, Nicole Joyé, Solenn Pruvost, Gulen Eda Utine, Koray Boduroglu, Patrick Nitschke, Laura FertittaChristel Thauvin-Robinet, Arnold Munnich, Valérie Cormier-Daire, Raoul Hennekam, Estelle Colin, Nurten Ayse Akarsu, Christine Bole-Feysot, Nicolas Cagnard, Alain Schmitt, Nicolas Goudin, Stanislas Lyonnet, Férechté Encha-Razavi, Jean Pierre Siffroi, Mark Winey, Nicholas Katsanis, Marie Gonzales, Michel Vekemans, Philip L. Beales, Tania Attié-Bitach

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

Original languageEnglish (US)
Pages (from-to)601-606
Number of pages6
JournalNature Genetics
Volume43
Issue number6
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

Fingerprint

Acrocallosal Syndrome
Hedgehogs
Mutation
Polydactyly
Cilia
Cleft Palate
Missense Mutation
Drosophila
Transcription Factors
Alleles
Phenotype
Brain
Ciliopathies
Hydrolethalus syndrome
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Putoux, A., Thomas, S., Coene, K. L. M., Davis, E. E., Alanay, Y., Ogur, G., ... Attié-Bitach, T. (2011). KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nature Genetics, 43(6), 601-606. https://doi.org/10.1038/ng.826

KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. / Putoux, Audrey; Thomas, Sophie; Coene, Karlien L.M.; Davis, Erica E.; Alanay, Yasemin; Ogur, Gönöl; Uz, Elif; Buzas, Daniela; Gomes, Céline; Patrier, Sophie; Bennett, Christopher L.; Elkhartoufi, Nadia; Frison, Marie Hélène Saint; Rigonnot, Luc; Joyé, Nicole; Pruvost, Solenn; Utine, Gulen Eda; Boduroglu, Koray; Nitschke, Patrick; Fertitta, Laura; Thauvin-Robinet, Christel; Munnich, Arnold; Cormier-Daire, Valérie; Hennekam, Raoul; Colin, Estelle; Akarsu, Nurten Ayse; Bole-Feysot, Christine; Cagnard, Nicolas; Schmitt, Alain; Goudin, Nicolas; Lyonnet, Stanislas; Encha-Razavi, Férechté; Siffroi, Jean Pierre; Winey, Mark; Katsanis, Nicholas; Gonzales, Marie; Vekemans, Michel; Beales, Philip L.; Attié-Bitach, Tania.

In: Nature Genetics, Vol. 43, No. 6, 01.06.2011, p. 601-606.

Research output: Contribution to journalArticle

Putoux, A, Thomas, S, Coene, KLM, Davis, EE, Alanay, Y, Ogur, G, Uz, E, Buzas, D, Gomes, C, Patrier, S, Bennett, CL, Elkhartoufi, N, Frison, MHS, Rigonnot, L, Joyé, N, Pruvost, S, Utine, GE, Boduroglu, K, Nitschke, P, Fertitta, L, Thauvin-Robinet, C, Munnich, A, Cormier-Daire, V, Hennekam, R, Colin, E, Akarsu, NA, Bole-Feysot, C, Cagnard, N, Schmitt, A, Goudin, N, Lyonnet, S, Encha-Razavi, F, Siffroi, JP, Winey, M, Katsanis, N, Gonzales, M, Vekemans, M, Beales, PL & Attié-Bitach, T 2011, 'KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes', Nature Genetics, vol. 43, no. 6, pp. 601-606. https://doi.org/10.1038/ng.826
Putoux A, Thomas S, Coene KLM, Davis EE, Alanay Y, Ogur G et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nature Genetics. 2011 Jun 1;43(6):601-606. https://doi.org/10.1038/ng.826
Putoux, Audrey ; Thomas, Sophie ; Coene, Karlien L.M. ; Davis, Erica E. ; Alanay, Yasemin ; Ogur, Gönöl ; Uz, Elif ; Buzas, Daniela ; Gomes, Céline ; Patrier, Sophie ; Bennett, Christopher L. ; Elkhartoufi, Nadia ; Frison, Marie Hélène Saint ; Rigonnot, Luc ; Joyé, Nicole ; Pruvost, Solenn ; Utine, Gulen Eda ; Boduroglu, Koray ; Nitschke, Patrick ; Fertitta, Laura ; Thauvin-Robinet, Christel ; Munnich, Arnold ; Cormier-Daire, Valérie ; Hennekam, Raoul ; Colin, Estelle ; Akarsu, Nurten Ayse ; Bole-Feysot, Christine ; Cagnard, Nicolas ; Schmitt, Alain ; Goudin, Nicolas ; Lyonnet, Stanislas ; Encha-Razavi, Férechté ; Siffroi, Jean Pierre ; Winey, Mark ; Katsanis, Nicholas ; Gonzales, Marie ; Vekemans, Michel ; Beales, Philip L. ; Attié-Bitach, Tania. / KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. In: Nature Genetics. 2011 ; Vol. 43, No. 6. pp. 601-606.
@article{5a8e251473c149448ab64d2f6e72b408,
title = "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes",
abstract = "KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.",
author = "Audrey Putoux and Sophie Thomas and Coene, {Karlien L.M.} and Davis, {Erica E.} and Yasemin Alanay and G{\"o}n{\"o}l Ogur and Elif Uz and Daniela Buzas and C{\'e}line Gomes and Sophie Patrier and Bennett, {Christopher L.} and Nadia Elkhartoufi and Frison, {Marie H{\'e}l{\`e}ne Saint} and Luc Rigonnot and Nicole Joy{\'e} and Solenn Pruvost and Utine, {Gulen Eda} and Koray Boduroglu and Patrick Nitschke and Laura Fertitta and Christel Thauvin-Robinet and Arnold Munnich and Val{\'e}rie Cormier-Daire and Raoul Hennekam and Estelle Colin and Akarsu, {Nurten Ayse} and Christine Bole-Feysot and Nicolas Cagnard and Alain Schmitt and Nicolas Goudin and Stanislas Lyonnet and F{\'e}recht{\'e} Encha-Razavi and Siffroi, {Jean Pierre} and Mark Winey and Nicholas Katsanis and Marie Gonzales and Michel Vekemans and Beales, {Philip L.} and Tania Atti{\'e}-Bitach",
year = "2011",
month = "6",
day = "1",
doi = "10.1038/ng.826",
language = "English (US)",
volume = "43",
pages = "601--606",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes

AU - Putoux, Audrey

AU - Thomas, Sophie

AU - Coene, Karlien L.M.

AU - Davis, Erica E.

AU - Alanay, Yasemin

AU - Ogur, Gönöl

AU - Uz, Elif

AU - Buzas, Daniela

AU - Gomes, Céline

AU - Patrier, Sophie

AU - Bennett, Christopher L.

AU - Elkhartoufi, Nadia

AU - Frison, Marie Hélène Saint

AU - Rigonnot, Luc

AU - Joyé, Nicole

AU - Pruvost, Solenn

AU - Utine, Gulen Eda

AU - Boduroglu, Koray

AU - Nitschke, Patrick

AU - Fertitta, Laura

AU - Thauvin-Robinet, Christel

AU - Munnich, Arnold

AU - Cormier-Daire, Valérie

AU - Hennekam, Raoul

AU - Colin, Estelle

AU - Akarsu, Nurten Ayse

AU - Bole-Feysot, Christine

AU - Cagnard, Nicolas

AU - Schmitt, Alain

AU - Goudin, Nicolas

AU - Lyonnet, Stanislas

AU - Encha-Razavi, Férechté

AU - Siffroi, Jean Pierre

AU - Winey, Mark

AU - Katsanis, Nicholas

AU - Gonzales, Marie

AU - Vekemans, Michel

AU - Beales, Philip L.

AU - Attié-Bitach, Tania

PY - 2011/6/1

Y1 - 2011/6/1

N2 - KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

AB - KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

UR - http://www.scopus.com/inward/record.url?scp=79957618775&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957618775&partnerID=8YFLogxK

U2 - 10.1038/ng.826

DO - 10.1038/ng.826

M3 - Article

C2 - 21552264

AN - SCOPUS:79957618775

VL - 43

SP - 601

EP - 606

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -