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Yayınlanmış 1 Ocak 2011 | Sürüm v1
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KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes

Oluşturanlar

  • 1. Hacettepe Univ, Fac Med, Dept Pediat, Pediat Genet Unit, TR-06100 Ankara, Turkey
  • 2. Ondokuz Mayis Univ, Dept Med Pediat Genet, Samsun, Turkey
  • 3. Hacettepe Univ, Fac Med, Dept Med Genet, Gene Mapping Lab, TR-06100 Ankara, Turkey
  • 4. Ctr Hosp CH Sud Francilien, Gynecol Serv, Evry, France
  • 5. Hop Necker Enfants Malad, INSERM, U 781, Paris, France
  • 6. Hop Armand Trousseau, Serv Genet & Embryol Med, AP HP, Paris, France
  • 7. Hop Necker Enfants Malad, Dept Genet, AP HP, Paris, France
  • 8. CH Victor Dupouy, Serv Anat & Cytol Pathol, Argenteuil, France
  • 9. Hop Necker Enfants Malad, Genom Core Facil, Imagine Fdn, Paris, France
  • 10. Univ Paris 05, Serv Bioinformat, Paris, France

Açıklama

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.

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