KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes

被引：173

作者：

Putoux, Audrey ^{[1
,2
]}

Thomas, Sophie ^{[1
,2
]}

Coene, Karlien L. M. ^{[3
,4
]}

Davis, Erica E. ^{[5
,6
]}

Alanay, Yasemin ^{[7
]}

Ogur, Gonul ^{[8
]}

Uz, Elif ^{[9
]}

Buzas, Daniela ^{[10
]}

Gomes, Celine ^{[1
]}

Patrier, Sophie ^{[11
]}

Bennett, Christopher L. ^{[8
]}

Elkhartoufi, Nadia ^{[12
]}

Saint Frison, Marie-Helene ^{[13
]}

Rigonnot, Luc ^{[10
]}

Joye, Nicole ^{[11
,14
]}

Pruvost, Solenn ^{[15
]}

Utine, Gulen Eda ^{[7
]}

Boduroglu, Koray ^{[7
]}

Nitschke, Patrick ^{[16
]}

Fertitta, Laura ^{[1
]}

Thauvin-Robinet, Christel ^{[17
]}

Munnich, Arnold ^{[1
,2
,12
]}

Cormier-Daire, Valerie ^{[1
,2
,12
]}

Hennekam, Raoul ^{[18
]}

Colin, Estelle ^{[19
]}

Akarsu, Nurten Ayse ^{[9
]}

Bole-Feysot, Christine ^{[15
]}

Cagnard, Nicolas ^{[16
]}

Schmitt, Alain ^{[20
]}

Goudin, Nicolas ^{[21
]}

Lyonnet, Stanislas ^{[1
,2
,12
]}

Encha-Razavi, Ferechte ^{[1
,2
,12
]}

Siffroi, Jean-Pierre ^{[11
,14
]}

Winey, Mark ^{[22
]}

Katsanis, Nicholas ^{[5
,23
]}

Gonzales, Marie ^{[11
,14
]}

Vekemans, Michel ^{[1
,2
,12
]}

Beales, Philip L. ^{[24
]}

Attie-Bitach, Tania ^{[1
,2
,12
]}

机构：

[1] Hop Necker Enfants Malad, INSERM, U 781, Paris, France

[2] Univ Paris 05, Paris, France

[3] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands

[5] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA

[6] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA

[7] Hacettepe Univ, Fac Med, Dept Pediat, Pediat Genet Unit, TR-06100 Ankara, Turkey

[8] Ondokuz Mayis Univ, Dept Med Pediat Genet, Samsun, Turkey

[9] Hacettepe Univ, Fac Med, Dept Med Genet, Gene Mapping Lab, TR-06100 Ankara, Turkey

[10] Ctr Hosp CH Sud Francilien, Gynecol Serv, Evry, France

[11] Hop Armand Trousseau, Serv Genet & Embryol Med, AP HP, Paris, France

[12] Hop Necker Enfants Malad, Dept Genet, AP HP, Paris, France

[13] CH Victor Dupouy, Serv Anat & Cytol Pathol, Argenteuil, France

[14] Univ Paris 06, Paris, France

[15] Hop Necker Enfants Malad, Genom Core Facil, Imagine Fdn, Paris, France

[16] Univ Paris 05, Serv Bioinformat, Paris, France

[17] CHU Dijon, Serv Genet, Dijon, France

[18] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands

[19] Hop Angers, Serv Genet, Angers, France

[20] Univ Paris 05, Inst Cochin, CNRS, UMR 8104, Paris, France

[21] Fac Med Necker Enfants Malad, IFR 94, Paris, France

[22] Univ Colorado, Boulder, CO 80309 USA

[23] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA

[24] UCL, Inst Child Hlth, Mol Med Unit, London, England

来源：

NATURE GENETICS | 2011年 / 43卷 / 06期

基金：

美国国家卫生研究院;

关键词：

SIGNAL-TRANSDUCTION; PROTEIN; CILIA; CILIOGENESIS; RPGRIP1L; JOUBERT; ALLELES; MECKEL;

D O I：

10.1038/ng.826

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：601 / U147

页数：7

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