KIF7 Mutations Cause Fetal Hydrolethalus and Acrocallosal Syndromes

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.

Citing Articles

Collaborative role of two distinct cilium-specific cytoskeletal systems in driving Hedgehog-responsive transcription factor trafficking.

Ku P, Sreeja J, Chadha A, Williams D, Engelke M, Subramanian R Sci Adv. 2025; 11(11):eadt5439.

PMID: 40073114 PMC: 11900865. DOI: 10.1126/sciadv.adt5439.

Hydrolethalus Syndrome: A Case of a Rare Congenital Disorder.

Belengeanu V, Marian D, Stana H, Cojocariu C, Popescu C, Lile I Diagnostics (Basel). 2025; 15(2.

PMID: 39857086 PMC: 11765131. DOI: 10.3390/diagnostics15020202.

Genetic and molecular mechanisms of hydrocephalus.

Deng X, Chen Y, Duan Q, Ding J, Wang Z, Wang J Front Mol Neurosci. 2025; 17():1512455.

PMID: 39839745 PMC: 11746911. DOI: 10.3389/fnmol.2024.1512455.

Identification of Pappa and Sall3 as Gli3 direct target genes acting downstream of cilia signaling in corticogenesis.

Basu S, Mautner L, Whiting K, Hasenpusch-Theil K, Borkowska M, Theil T Cereb Cortex. 2024; 34(12).

PMID: 39716738 PMC: 11666469. DOI: 10.1093/cercor/bhae480.

Expanding the Phenotypic Spectrum of Pathogenic Variants: From Joubert Syndrome to Hydrolethalus Syndrome.

Deconte D, Diniz B, Hartmann J, de Souza M, Zottis L, Gazzola Zen P Int J Mol Sci. 2024; 25(14).

PMID: 39063141 PMC: 11277298. DOI: 10.3390/ijms25147900.

References

Zaghloul N, Liu Y, Gerdes J, Gascue C, Oh E, Leitch C . Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome. Proc Natl Acad Sci U S A. 2010; 107(23):10602-7. PMC: 2890780. DOI: 10.1073/pnas.1000219107. View

Davis E, Zhang Q, Liu Q, Diplas B, Davey L, Hartley J . TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011; 43(3):189-96. PMC: 3071301. DOI: 10.1038/ng.756. View

Salonen R, Herva R, Norio R . The hydrolethalus syndrome: delineation of a "new", lethal malformation syndrome based on 28 patients. Clin Genet. 1981; 19(5):321-30. DOI: 10.1111/j.1399-0004.1981.tb00718.x. View

Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen J, Phamluong K . The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009; 19(15):1320-6. DOI: 10.1016/j.cub.2009.06.046. View

Baker K, Beales P . Making sense of cilia in disease: the human ciliopathies. Am J Med Genet C Semin Med Genet. 2009; 151C(4):281-95. DOI: 10.1002/ajmg.c.30231. View

Schinzel A, Schmid W . Hallux duplication, postaxial polydactyly, absence of the corpus callosum, severe mental retardation, and additional anomalies in two unrelated patients: a new syndrome. Am J Med Genet. 1980; 6(3):241-9. DOI: 10.1002/ajmg.1320060308. View

Leitch C, Zaghloul N, Davis E, Stoetzel C, Diaz-Font A, Rix S . Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008; 40(4):443-8. DOI: 10.1038/ng.97. View

Badano J, Leitch C, Ansley S, May-Simera H, Lawson S, Lewis R . Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature. 2005; 439(7074):326-30. DOI: 10.1038/nature04370. View

Mee L, Honkala H, Kopra O, Vesa J, Finnila S, Visapaa I . Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1. Hum Mol Genet. 2005; 14(11):1475-88. DOI: 10.1093/hmg/ddi157. View

10.

Goetz S, Anderson K . The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet. 2010; 11(5):331-44. PMC: 3121168. DOI: 10.1038/nrg2774. View

11.

Tay S, Ingham P, Roy S . A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development. 2005; 132(4):625-34. DOI: 10.1242/dev.01606. View

12.

Kim J, Lee J, Heynen-Genel S, Suyama E, Ono K, Lee K . Functional genomic screen for modulators of ciliogenesis and cilium length. Nature. 2010; 464(7291):1048-51. PMC: 2929961. DOI: 10.1038/nature08895. View

13.

Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K . The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007; 39(7):875-81. DOI: 10.1038/ng2039. View

14.

Schinzel A, Kaufmann U . The acrocallosal syndrome in sisters. Clin Genet. 1986; 30(5):399-405. DOI: 10.1111/j.1399-0004.1986.tb01897.x. View

15.

Khanna H, Davis E, Murga-Zamalloa C, Estrada-Cuzcano A, Lopez I, den Hollander A . A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet. 2009; 41(6):739-45. PMC: 2783476. DOI: 10.1038/ng.366. View

16.

Robbins D, Nybakken K, Kobayashi R, Sisson J, Bishop J, Therond P . Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell. 1997; 90(2):225-34. DOI: 10.1016/s0092-8674(00)80331-1. View

17.

Valente E, Logan C, Mougou-Zerelli S, Lee J, Silhavy J, Brancati F . Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet. 2010; 42(7):619-25. PMC: 2894012. DOI: 10.1038/ng.594. View

18.

Liem Jr K, He M, Ocbina P, Anderson K . Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci U S A. 2009; 106(32):13377-82. PMC: 2726420. DOI: 10.1073/pnas.0906944106. View

19.

Wolff C, Roy S, Ingham P . Multiple muscle cell identities induced by distinct levels and timing of hedgehog activity in the zebrafish embryo. Curr Biol. 2003; 13(14):1169-81. DOI: 10.1016/s0960-9822(03)00461-5. View

20.

Kalderon D . Hedgehog signaling: Costal-2 bridges the transduction gap. Curr Biol. 2004; 14(2):R67-9. DOI: 10.1016/j.cub.2003.12.047. View