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.
authors.affiliation: INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Putoux
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Karlien L M
authors.initials: KL
authors.lastname: Coene
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Gönül
authors.initials: G
authors.lastname: Ogur
authors.forename: Elif
authors.initials: E
authors.lastname: Uz
authors.forename: Daniela
authors.initials: D
authors.lastname: Buzas
authors.forename: Céline
authors.initials: C
authors.lastname: Gomes
authors.forename: Sophie
authors.initials: S
authors.lastname: Patrier
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhartoufi
authors.forename: Marie-Hélène Saint
authors.initials: MH
authors.lastname: Frison
authors.forename: Luc
authors.initials: L
authors.lastname: Rigonnot
authors.forename: Nicole
authors.initials: N
authors.lastname: Joyé
authors.forename: Solenn
authors.initials: S
authors.lastname: Pruvost
authors.forename: Gulen Eda
authors.initials: GE
authors.lastname: Utine
authors.forename: Koray
authors.initials: K
authors.lastname: Boduroglu
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Laura
authors.initials: L
authors.lastname: Fertitta
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Estelle
authors.initials: E
authors.lastname: Colin
authors.forename: Nurten Ayse
authors.initials: NA
authors.lastname: Akarsu
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Alain
authors.initials: A
authors.lastname: Schmitt
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goudin
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Férechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Siffroi
authors.forename: Mark
authors.initials: M
authors.lastname: Winey
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D055673:Acrocallosal Syndrome / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D002552:Cerebral Ventricles / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000235:genetics; D003241:Consanguinity; D005260:Female; D006228:Hand Deformities, Congenital / Q000196:embryology / Q000235:genetics / Q000473:pathology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D006849:Hydrocephalus / Q000196:embryology / Q000235:genetics / Q000473:pathology; D007223:Infant; D016547:Kinesins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D053823:Hedgehog Proteins; C502069:KIF7 protein, human; D016547:Kinesins