HGNC Approved Gene Symbol: KIF7
SNOMEDCT: 715951007;
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38) : 15:89,617,309-89,663,049 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | ?Al-Gazali-Bakalinova syndrome | 607131 | Autosomal recessive | 3 |
| ?Hydrolethalus syndrome 2 | 614120 | Autosomal recessive | 3 | |
| Acrocallosal syndrome | 200990 | Autosomal recessive | 3 | |
| Joubert syndrome 12 | 200990 | Autosomal recessive | 3 |
The KIF7 gene encodes a cilia-associated protein belonging to the kinesin family that plays a role in the hedgehog (see, e.g., SHH; 600725) signaling pathway through the regulation of GLI (see, e.g., GLI1; 165220) transcription factors (summary by Putoux et al., 2011). The KIF7 gene also plays a role in the regulation of microtubule acetylation and stabilization (Dafinger et al., 2011).
By database searching using Drosophila Cos2 and mouse Kif7 as probes, Katoh and Katoh (2004) identified full-length KIF7. The deduced 1,343-amino protein shares 43.6% amino acid identity with KIF27 (611253) and 61.6% identity with KIF27 over the kinesin motor domain. KIF7 and KIF27 also share an additional region of high homology, which the authors called the KIF7-KIF27 homologous (KIF727H) domain. EST database analysis showed KIF7 mRNA expression in embryonic stem cells, melanotic melanoma, and Jurkat T cells.
Katoh and Katoh (2004) determined that the KIF7 gene contains at least 19 exons.
By genomic sequence analysis, Katoh and Katoh (2004) mapped the KIF7 gene to chromosome 15q26.1.
Dafinger et al. (2011) demonstrated that KIF7 coprecipitated with NPHP1 (607100).
Using immunofluorescence analysis, He et al. (2014) showed that endogenous Kif7 localized to primary cilia tips in mouse embryos and mouse embryonic fibroblasts (MEFs), independently of Shh pathway proteins. Immunofluorescence and electron microscopic analyses revealed that Kif7-null embryonic neural epithelium and cultured MEFs had abnormally long, twisted, unstable cilia with decreased levels of tubulin modification. However, intraflagellar transport (IFT) was normal in Kif7-null cilia. Coimmunoprecipitation analysis showed that Kif7 formed a homodimer and colocalized and interacted with microtubules in transfected HEK293T cells. Domain mapping revealed that microtubule association and dimerization depended on the motor domain and first coiled-coil domain of Kif7. Fluorescence microscopy-based assays demonstrated that purified recombinant Kif7 bound directly to microtubules and preferentially associated with their growing plus ends, where it inhibited microtubule polymerization in an ATP hydrolysis-dependent manner. The pattern of IFT particle movement was perturbed in Kif7-null MEFs, and multiple compartments with tip-like properties became distributed along the cilia. Immunofluorescence analysis demonstrated that the core hedgehog signaling components Gli2 (165230) and Sufu (607035) localized abnormally in puncta along the axoneme in Kif7-null MEFs, whereas in wildtype cells they accumulated at cilia tips.
Hydrolethalus Syndrome 2
By genomewide linkage analysis followed by candidate gene analysis of a consanguineous Algerian family with hydrolethalus syndrome-2 (HLS2; 614120), Putoux et al. (2011) identified a homozygous deletion in the KIF7 gene (611254.0001) in affected members. There were 4 affected sib fetuses, ranging in age from 11 to 15 weeks' gestation. Two had anencephaly, 1 of whom had postaxial polydactyly of an upper limb and preaxial polydactyly of both lower limbs. The 2 other fetuses had hydrocephaly, 1 also with arhinencephaly, postaxial polydactyly of the upper limb and pre- and postaxial polydactyly of the lower limbs. Two had cleft palate and hallux duplication, and 1 had micrognathia. Neuropathologic examination of 1 fetus showed widened ventricles and midbrain-hindbrain malformation suggestive of the molar tooth sign. The molecular findings indicated that HLS2 is a ciliopathy. Transcriptome analysis from these affected fetuses showed upregulation of direct and/or secondary targets of GLI1 (165220), GLI2 (165230), and GLI3 (165240), although these transcription factors were normally expressed. Thus, there was an overall increase in SHH-mediated target gene expression.
Acrocallosal Syndrome
By genomewide linkage analysis followed by candidate gene sequencing, Putoux et al. (2011) identified 3 nonsense and 5 frameshift mutations in the KIF7 gene (see, e.g., 611254.0001-611254.0005) in patients with acrocallosal syndrome (ACLS; 200990) from 6 families and in 2 individual patients. The mutations were presumably homozygous. Most affected individuals had macrocephaly, mental retardation, abnormal facies, and brain abnormalities including dilated ventricles, corpus callosum agenesis or hypoplasia, and a superior vermis dysgenesis resulting in the molar tooth sign in 4 cases. Five affected individuals had postaxial polydactyly of the hands. In the feet, polydactyly was preaxial; hallux duplication was postaxial or preaxial and postaxial. Cultured fibroblasts from 1 patient showed the presence of primary cilia with normal components, but the cilia were longer in patient cells compared to controls, suggesting that KIF7 may be involved in regulating cilia length. The findings indicated that ACLS is a ciliopathy.
Dafinger et al. (2011) identified a homozygous truncating mutation in the KIF7 gene (611254.0006) in 2 Egyptian sibs with Joubert syndrome-12 (JBTS12; see 200990). A third patient with the disorder had a heterozygous mutation (611254.0007), but a second pathogenic allele was not identified. A fourth patient with Joubert syndrome had 2 pathogenic mutations in the TMEM67 gene (609884.0013, 609884.0024), consistent with JBTS6 (610688), as well as a heterozygous mutation in the KIF7 gene (611254.0008). Knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and decreased microtubular dynamics. The findings indicated that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to Joubert syndrome.
Al-Gazali-Bakalinova Syndrome
By whole-exome sequencing in the family with macrocephaly, multiple epiphyseal dysplasia, and distinctive facies (AGBK; 607131) described by Al-Gazali and Bakalinova (1998), Ali et al. (2012) identified homozygosity for a missense mutation (N1060S; 611254.0009) at a conserved residue in the KIF7 gene. The mutation segregated with the phenotype in the family and was not found in 188 mixed Omani/UAE ethnically matched controls.
Heterozygous KIF7 Mutations in Ciliopathies
Putoux et al. (2011) identified 8 different heterozygous missense mutations in the KIF7 gene in 8 patients with ciliopathies, including Bardet-Biedl syndrome (BBS; 209900), Meckel syndrome (MKS; 249000), Joubert syndrome (JBTS; 213300), Pallister-Hall syndrome (PHS; 146510), and OFD6 (277170). Four of these patients had additional pathogenic mutations in other BBS genes. Rescue studies of somites in morphant zebrafish embryos demonstrated that the heterozygous missense mutations were hypomorphs, and Putoux et al. (2011) concluded that these alleles may contribute to or exacerbate the phenotype of other ciliopathies, particularly BBS.
In mice, Liem et al. (2009) demonstrated that Kif7 is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (SMOH; 601500) to Gli transcription factors, and has both positive and negative roles in Shh (600725) signal transduction. Mouse Kif7 activity depends on the presence of cilia. Kif7 localizes to base of the primary cilium in the absence of Shh, and activation of the Shh pathway promotes trafficking of Kif7 from the base to the tip of the cilium. The results suggested that Kif7 is a core regulator of Shh signaling that may also act as a ciliary motor. A murine mutation, matariki (maki), was identified that caused an expanded motor neuron domain in the embryonic day 10.5 (E10.5) neural tube. Maki mutants died at the end of gestation. The mutant was due to a L130P missense mutation in the motor domain of Kif7 that resulted in a loss of Kif7 activity and an increase in activity of the Shh pathway.
Putoux et al. (2019) found that deletion of Kif7 in mice resulted in lethality before birth or at birth. Kif7 -/- mouse embryos exhibited abnormal development of corpus callosum (CC), exencephaly, skeletal malformations, neural patterning defects, and microphthalmia, recapitulating the phenotype of ACLS in human. Increased activity of Gli3 repressor (GLI3R) rescued these defects in Kif7 -/- mice in a dose-dependent manner. Further analysis revealed that Kif7 regulated the distribution of guidepost neurons and glial cells at the midline by modulating Gli3r activity, demonstrating that decreased Gli3r signaling was responsible for the ACLS features in Kif7 -/- mice. Kif7 -/- embryos showed increased expression of Fgf8 (600483) in the ventral medial pallium of developing brain compared with restricted Fgf8 expression in commissural plate in wildtype. Reducing Fgf8 expression partially rescued the defects in CC formation and guidepost neuron organization in Kif7 -/- embryos. These findings demonstrated that Fgf8 signaling acted downstream of Kif7 in anterior brain during CC formation through proper organization of astroglial cells and guidepost neurons at the telencephalic midline.
Hydrolethalus Syndrome 2
By genomewide linkage analysis followed by candidate gene analysis of a consanguineous Algerian family with hydrolethalus syndrome-2 (HLS2; 614120), Putoux et al. (2011) identified a homozygous 2-bp deletion (2896_2897del) in the beginning of exon 15 of the KIF7 gene. There were 4 sib fetuses ranging in age from 11 to 15 weeks' gestation. Two had anencephaly, 1 of whom had postaxial polydactyly of an upper limb and preaxial polydactyly of both lower limbs. The 2 other fetuses had hydrocephaly, 1 also with arhinencephaly, postaxial polydactyly of the upper limbs, and pre- and postaxial polydactyly of the lower limbs. Two had cleft palate and hallux duplication, and 1 had micrognathia. Neuropathologic examination of 1 fetus showed widened ventricles and midbrain-hindbrain malformation suggestive of the molar tooth sign. RT-PCR analysis of RNA extracted from lungs of affected fetuses showed no aberrant splicing or RNA decay. Transcriptome analysis from affected fetuses showed upregulation of direct and/or secondary targets of GLI1 (165220), GLI2 (165230), and GLI3 (165240).
Acrocallosal Syndrome
Putoux et al. (2011) identified the same 2-bp deletion in the KIF7 gene in a 15-year-old Algerian boy with acrocallosal syndrome (ACLS; 200990) who was born of consanguineous parents. This patient had mental retardation, thin corpus callosum, molar tooth sign on brain imaging, preaxial polydactyly of the lower limbs, hypertelorism, retrognathia, and dental anomalies.
In a 4-year-old Turkish boy, born of consanguineous parents, with acrocallosal syndrome (ACLS; 200990), Putoux et al. (2011) identified a homozygous 460C-T transition in exon 3 of the KIF7 gene, resulting in an arg154-to-ter (R154X) substitution in the kinesin motor domain. This patient had mental retardation, dysmorphic facial features, molar tooth sign on brain imaging, agenesis of the corpus callosum, and preaxial polydactyly of one lower limb. Cultured fibroblasts from this patient showed the presence of primary cilia with normal components, but the cilia were longer in patient cells compared to controls, suggesting that KIF7 may be involved in regulating cilia length.
In a 26-month-old Turkish boy with acrocallosal syndrome (ACLS; 200990), Putoux et al. (2011) identified a homozygous 3001C-T transition in exon 15 of the KIF7 gene, resulting in a gln1001-to-ter (Q1001X) substitution in the coiled-coil domain.
In a 12-year-old Finnish boy with acrocallosal syndrome (ACLS; 200990), Putoux et al. (2011) identified a homozygous 1-bp duplication (587dupT) in exon 4 of the KIF7 gene in the kinesin motor domain. The mutation was predicted to result in a frameshift and premature termination.
In a 9-year-old Pakistani boy, born of consanguineous parents, with acrocallosal syndrome (ACLS; 200990), Putoux et al. (2011) identified a homozygous 1-bp deletion (687delG) in exon 4 of the KIF7 gene in the kinesin motor domain, resulting in a frameshift and premature termination.
In 2 Egyptian sibs, born of consanguineous parents, with Joubert syndrome-12 (JBTS12; see 200990), Dafinger et al. (2011) identified a homozygous 1-bp deletion (217delG) in exon 1 of the KIF7 gene, predicted to result in a truncated protein or nonsense-mediated mRNA decay. The mutation was not found in 104 controls. The patients had mental retardation, molar tooth sign on brain MRI, and dysmorphic facial features, including hypertelorism, triangular mouth, downslanting palpebral fissures, low-set ears, and prominent forehead. One patient had ataxia, agenesis of the corpus callosum, and polydactyly.
In a German boy with Joubert syndrome-12 (JBTS12; see 200990), Dafinger et al. (2011) identified a heterozygous 1-bp deletion in exon 3 of the KIF7 gene, resulting in truncation. A second pathogenic allele was not identified. The patient had moderate developmental delay and the molar tooth sign on brain MRI, but did not have dysmorphic features.
In a German patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 811delG mutation in the KIF7 gene consistent with JBTS12, and a heterozygous mutation in the CEP41 gene (R179H; 610523.0004) consistent with JBTS15 (614464). The patient had hypotonia, ataxia, mental retardation, oculomotor apraxia, breathing difficulties, and the molar tooth sign on brain imaging, but no liver, renal, or retinal involvement.
This variant is classified as a variant of unknown significance because its contribution to the phenotype of Joubert syndrome has not been confirmed.
In a German girl with Joubert syndrome, Dafinger et al. (2011) identified a heterozygous 12-bp deletion (3986del12) in the last KIF7 exon, predicting an in-frame loss of 4 residues in the putative cargo domain. She also had 2 pathogenic missense mutations in the TMEM67 gene (I833T, 609884.0013 and P358L, 609884.0024), consistent with JBTS6 (610688). The patient had mental retardation, molar tooth sign on brain MRI, ataxia, hypertelorism, low-set ears, coloboma, and elevated liver enzymes.
By whole-exome sequencing in the family described by Al-Gazali and Bakalinova (1998) with Al-Gazali-Bakalinova syndrome (AGBK; 607131), Ali et al. (2012) identified homozygosity for a c.3179A-G transition (c.3179A-G, NM_198525.2) in the KIF7 gene, resulting in an asn1060-to-ser (N1060S) substitution. The mutation segregated with the phenotype in the family and was absent from 188 mixed Omani/UAE ethnically matched controls. The N1060 residue is located after the SMC domain of KIF7 and is absolutely conserved in KIF7 family members. The N1060S variant was not present in the ExAC database (1/21/2016) (Hamosh, 2016).
Al-Gazali, L. I., Bakalinova, D. Autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Clin. Dysmorph. 7: 177-184, 1998. [PubMed: 9689990] [Full Text: https://doi.org/10.1097/00019605-199807000-00004]
Ali, B. R., Silhavy, J. L., Akawi, N. A., Gleeson, J. G., Al-Gazali, L. A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Orphanet J. Rare Dis. 7: 27, 2012. Note: Electronic Article. [PubMed: 22587682] [Full Text: https://doi.org/10.1186/1750-1172-7-27]
Dafinger, C., Liebau, M. C., Elsayed, S. M., Hellenbroich, Y., Boltshauser, E., Korenke, G. C., Fabretti, F., Janecke, A. R., Ebermann, I., Nurnberg, G., Nurnberg, P., Zentgraf, H., Koerber, F., Addicks, K., Elsobky, E., Benzing, T., Schermer, B., Bolz, H. J. Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics. J. Clin. Invest. 121: 2662-2667, 2011. [PubMed: 21633164] [Full Text: https://doi.org/10.1172/JCI43639]
Hamosh, A. Personal Communication. Baltimore, Md. 1/21/2016.
He, M., Subramanian, R., Bangs, F., Omelchenko, T., Liem, K. F., Jr., Kapoor, T. M., Anderson, K. V. The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nature Cell Biol. 16: 663-672, 2014. [PubMed: 24952464] [Full Text: https://doi.org/10.1038/ncb2988]
Katoh, Y., Katoh, M. Characterization of KIF7 gene in silico. Int. J. Oncol. 25: 1881-1886, 2004. [PubMed: 15547730]
Lee, J. E., Silhavy, J. L., Zaki, M. S., Schroth, J., Bielas, S. L., Marsh, S. E., Olvera, J., Brancati, F., Iannicelli, M., Ikegami, K., Schlossman, A. M., Merriman, B., and 18 others. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nature Genet. 44: 193-199, 2012. [PubMed: 22246503] [Full Text: https://doi.org/10.1038/ng.1078]
Liem, K. F., Jr., He, M., Ocbina, P. J. R., Anderson, K. V. Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc. Nat. Acad. Sci. 106: 13377-13382, 2009. [PubMed: 19666503] [Full Text: https://doi.org/10.1073/pnas.0906944106]
Putoux, A., Baas, D., Paschaki, M., Morle, L., Maire, C., Attie-Bitach, T., Thomas, S., Durand, B. Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice. Hum. Molec. Genet. 28: 877-887, 2019. [PubMed: 30445565] [Full Text: https://doi.org/10.1093/hmg/ddy392]
Putoux, A., Thomas, S., Coene, K. L., Davis, E. E., Alanay, Y., Ogur, G., Uz, E., Buzas, D., Gomes, C., Patrier, S., Bennett, C. L., Elkhartoufi, N., and 27 others. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nature Genet. 43: 601-606, 2011. [PubMed: 21552264] [Full Text: https://doi.org/10.1038/ng.826]