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.

Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics

“…Mice harboring homozygous mutations in the Kif7 gene have CDH and lung hypoplasia as well as defects affecting the cardiac, skeletal, and central nervous systems (24). Homozygous KIF7 mutations have been associated with several severe, multisystem disorders in humans, without CDH (25,26). Both patients in our cohort with KIF7 variants, however, have isolated CDH, suggesting that heterozygous variants in this gene may result in increased susceptibility to CDH.…”

New insights into genotype–phenotype correlation for GLI3 mutations

“…Overlapping features with acrocallosal syndrome (ACLS, MIM# 200990) associating callosal dysgenesis, hypertelorism, intellectual disability and PD 23 are explained by an impaired GLI3 processing in patients with KIF7 mutations. 24 Facial dysmorphism, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis of ACLS. Conversely, two GLI3 mutated cases with corpus callosum dysgenesis have been reported as ACLS 25,26 and a third similar patient has been reported by Johnston et al 10 All three mutations were missense and clustered in the same region between aa 903 and 934 suggesting a potential severe phenotype associated with alterations of this region.…”

A large duplication involving the IHH locus mimics acrocallosal syndrome

“…Homozygous Kif7 mutant mouse embryos, as well as human ACS patients show a decrease in Gli3R levels, leading to ectopic derepression of Gli3 target genes and to a polydactyly phenotype. 20,26 Evidently, the overlapping phenotypes of ACS, GCPS and our cases could thus be explained by alterations of Hh signaling and its common effector Gli3. In the future, it will be interesting to identify target genes of Gli3 that have a role in digit patterning.…”

“…20 Very recently, Putoux et al 20 described autosomal recessive mutations in KIF7 in families with ACS. Although the pattern of inheritance in our family was clearly not recessive, the index patient met the suggested clinical diagnostic criteria for ACS, and despite the absence of hallux duplication, a common feature of ACS, 20 the diagnosis of ACS in the index patient was convincing, also supported by the severe mental retardation and agenesis of the corpus callosum, which is to be found in almost all cases with ACS. 21 However, the extensive syndactyly seen in our patient is a feature more frequently seen in patients with Greig cephalopolysyndactyly syndrome (GCPS, MIM 175700).…”