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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.

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Figure 1: Phenotypes of individuals with KIF7 mutations.
Figure 2: Missense KIF7 variants are pathogenic and may interact genetically with other BBS loci.
Figure 3: Hedgehog signaling in individuals with KIF7 mutations.

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Acknowledgements

We are grateful to families and to the French Society of Fetal Pathology (SOFFOET) for participating in the study, to C. Dubourg, P. Wieacker, B. Leroy, N. Laurent, V. Fermeaux, S. Odent for fetuses' referral and to A. Schinzel and A. David for ACLS samples. We thank M. Zarhrate, A. Aguilar, N. Spasky and L. Besse for technical help. We thank N. Boddaert for helpful discussion. This work was supported by grants from ANR (FETALCILIOPATHIES number 07-MRAR-010-02 and FOETOCILPATH number BLAN-1122-01), E-RARE (Cranirare number 07-ERare-001-01) the Scientific and Technological Research Council of Turkey (TUBITAK, grant number 108S420 to N.A.A.), the US National Institutes of Health grant R01HD04260 from the National Institute of Child Health and Development (N.K.), R01DK072301 from the National Institute of Diabetes, Digestive and Kidney Disorders (N.K.) and the European Union (EU-SYSCILIA; E.E.D., N.K. and P.L.B.). A.P. was granted a fellowship from the Académie de Médecine. S.T. is supported by NIH 'Hereditary Basis of Neural Tube Defects' N° NS039818-07 to M. Speer. K.L.M.C. is supported by the Huygens Scholarship Programme and the Netherlands Organization for Scientific Research (NWO Toptalent-021.001.014). M.W. was a fellow of the Guggenheim Foundation and was supported by the March of Dimes Foundation (1-FY07-422). P.L.B. is a Wellcome Trust Senior Research Fellow. N.K. is a Distinguished George W. Brumley Professor.

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S. Patrier, M.-H.S.F., F.E.-R. and J.-P.S. performed the fetal examinations. N.J. did the fetal karyotyping. L.R. and M.G. referred the HLS family. D.B. did the ultrasound diagnosis. G.O., Y.A., G.E.U., K.B., R.H., P.L.B., C.T., V.C.-D. and E.C. referred subjects. C.L.B., M.W., K.C., N.A.A., C.B.-F., E.U. and P.N. performed the homozygosity mapping and LOD score calculation. C.G., N.E., L.F., K.L.M.C., M.W. and C.B.-F. performed linkage and sequence analyses. S. Pruvost and E.U. did the chip experiments. S.T. and N.C. performed the expression analysis. A.S. performed the electron microscopy. N.G. and A.P. performed the confocal microscopy and measurement of cilia length. E.E.D. and N.K. did the zebrafish experiments. A.M., S.L. and M.V. advised the work. T.A.-B. designed the study and wrote the manuscript.

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Correspondence to Tania Attié-Bitach.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 and Supplementary Tables 1–4. (PDF 335 kb)

Supplementary Table 5

List of genes deregulated in fetuses with KIF7 mutations (XLS 3780 kb)

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Putoux, A., Thomas, S., Coene, K. et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet 43, 601–606 (2011). https://doi.org/10.1038/ng.826

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