Kif7 Mutations Cause Fetal Hydrolethalus and Acrocallosal Syndromes
Tarih
2011Yazar
Putoux, Audrey
Thomas, Sophie
Coene, Karlien L. M.
Davis, Erica E.
Alanay, Yasemin
Ogur, Gonul
Uz, Elif
Buzas, Daniela
Gomes, Celine
Patrier, Sophie
Bennett, Christopher L.
Elkhartoufi, Nadia
Saint Frison, Marie-Helene
Rigonnot, Luc
Joye, Nicole
Pruvost, Solenn
Utine, Gulen Eda
Boduroglu, Koray
Nitschke, Patrick
Fertitta, Laura
Thauvin-Robinet, Christel
Munnich, Arnold
Cormier-Daire, Valerie
Hennekam, Raoul
Colin, Estelle
Akarsu, Nurten Ayse
Bole-Feysot, Christine
Cagnard, Nicolas
Schmitt, Alain
Goudin, Nicolas
Lyonnet, Stanislas
Encha-Razavi, Ferechte
Siffroi, Jean-Pierre
Winey, Mark
Katsanis, Nicholas
Gonzales, Marie
Vekemans, Michel
Beales, Philip L.
Attie-Bitach, Tania
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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.