NovelKIF7mutations extend the phenotypic spectrum of acrocallosal syndrome

Putoux, Audrey; Nampoothiri, Sheela; Laurent, Nicole; Cormier‐Daire, Valérie; Beales, Philip L.; Schinzel, Albert; Bartholdi, Deborah; Alby, Caroline; Thomas, Sophie; Elkhartoufi, Nadia; Ichkou, Amale; Litzler, Julie; Münnich, Arnold; Encha‐Razavi, Férechté; Kannan, R.; Faivre, Laurence; Boddaert, Nathalie; Rauch, Anita; Vekemans, Michel; Attié‐Bitach, Tania

doi:10.1136/jmedgenet-2012-101016

Cited by 34 publications

(42 citation statements)

References 29 publications

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“…Interestingly, KIF7 is a ciliary protein that promotes the localization and appropriate regulation of SUFU and GLI proteins at the ciliary tip. 19,51 In the absence of functional KIF7, the ciliary tip compartment becomes disorganized, leading to the formation of ectopic tip-like compartments where GLI-SUFU complexes localize and are inappropriately activated even in the absence of SHH ligand. 52 The same constellation of cranio-facial abnormalities along with developmental delay and polysyndactyly is detected in GCPS, in which heterozygous GLI3 variants result in reduced levels of Gli3R.…”

Section: Discussionmentioning

confidence: 99%

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Mori

Romani²,

D’Arrigo

et al. 2017

The American Journal of Human Genetics

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The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild ''molar tooth sign''), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

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Section: Discussionmentioning

confidence: 99%

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Mori

Romani²,

D’Arrigo

et al. 2017

The American Journal of Human Genetics

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“…In the two previous series reported by Johnston et al,9,10 four GCPS patients with corpus callosum dysgenesis were also carrying a GLI3 truncating mutation lying in the C-terminal domain of the protein further confirming our finding that corpus callosum dysgenesis is fully part of GCPS spectrum and is mainly caused by terminal truncating 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.…”

Section: Discussionmentioning

confidence: 99%

New insights into genotype–phenotype correlation for GLI3 mutations

et al. 2014

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The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

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“…After adding 5 ACLS patients with novel KIF7 mutations by the same group, however, a more variable expression of the phenotype emerged. While craniofacial dysmorphism was present in all 5 cases, one patient did not show a corpus callosum anomaly and another one did not exhibit polydactyly [Putoux et al, 2012]. Furthermore, compound heterozygous cases were presented for the first time.…”

Section: Kif7 Mutations In the Literature And Clinical Overlap With Omentioning

confidence: 90%

“…In their second study, 3 of 5 patients again presented with MTS [Putoux et al, 2012]. JS and related disorders are a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis, with MTS as the characteristic neuroradiological finding and accompanying neurological symptoms such as a dysregulation of breathing pattern and developmental delay.…”

Section: Kif7 Mutations In the Literature And Clinical Overlap With Omentioning

confidence: 99%

Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature

Ibisler

Hehr

Barth³

et al. 2015

Mol Syndromol

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Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway.

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NovelKIF7mutations extend the phenotypic spectrum of acrocallosal syndrome

Cited by 34 publications

References 29 publications

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

New insights into genotype–phenotype correlation for GLI3 mutations

Novel <b><i>KIF7</i></b> Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature

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