Biallelic variants in KIF14 cause intellectual disability with microcephaly

Makrythanasis, Periklis; Maroofian, Reza; Stray-Pedersen, Asbjørg; Musaev, Damir; Zaki, Maha S.; Mahmoud, Iman G.; Selim, Laila; Elbadawy, Amera; Jhangiani, Shalini N.; Akdemir, Zeynep H. Coban; Gambin, Tomasz; Sorte, Hanne Sørmo; Heiberg, Arvid; McEvoy‐Venneri, Jennifer; James, Kiely N.; Stanley, Valentina; Belandres, Denice; Guipponi, Michel; Santoni, Federico; Ahangari, Najmeh; Tara, Fatemeh; Doosti, Mohammad; Iwaszkiewicz, Justyna; Zoete, Vincent; Backe, Paul Hoff; Hamamy, Hanan; Gleeson, Joseph G.; Lupski, James R.; Karimiani, Ehsan Ghayoor; Antonarakis, Stylianos E.

doi:10.1038/s41431-017-0088-9

Cited by 52 publications

(41 citation statements)

References 37 publications

(45 reference statements)

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“…Previous studies have demonstrated that the depletion of KIF14 may induce the incompletion of cytokinesis and lead to multi- nucleation ( 19 , 20 ). Additionally, the homozygous mutation of KIF14 may result in autosomal recessive primary microcephaly ( 21 , 22 ).…”

Section: Introductionmentioning

confidence: 99%

KIF14 promotes cell proliferation via activation of Akt and is directly targeted by miR-200c in colorectal cancer

et al. 2018

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As a mitotic kinesin, kinesin family member 14 (KIF14) has been reported to serve oncogenic roles in a variety of malignancies; however, its functional role and regulatory mechanisms in colorectal cancer (CRC) remain unclear. In the present study, KIF14 was observed to be markedly overexpressed in CRC, and this upregulation was associated with tumor size and marker of proliferation Ki-67 immunostaining scores. Gain- and loss-of-function experiments were applied to identify the function of KIF14 in CRC progression. In vitro and in vivo assays revealed that KIF14 promoted CRC cell proliferation and accelerated the cell cycle via activation of protein kinase B. In addition, the present study investigated the potential mechanisms underlying KIF14 overexpression in CRC. Bioinformatics analyses and validation experiments, including reverse transcription-quantitative polymerase chain reaction, western blotting and a Dual-Luciferase reporter assay, demonstrated that, in addition to genomic amplification and transcriptional activation, KIF14 was regulated by microRNA (miR)-200c at the post-transcriptional level. Rescue experiments further demonstrated that decreased miR-200c expression could facilitate KIF14 to exert its pro-proliferative role. The expression of miR-200c was negatively correlated with KIF14 in CRC specimens. Collectively, the findings of the present study demonstrated the oncogenic role of KIF14 in colorectal tumorigenesis, and also revealed a complexity of regulatory mechanisms mediating KIF14 overexpression, which may provide insight for developing novel treatments for patients with CRC.

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Section: Introductionmentioning

confidence: 99%

KIF14 promotes cell proliferation via activation of Akt and is directly targeted by miR-200c in colorectal cancer

et al. 2018

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“…Based on the preponderance of evidence from in vitro and xenograft studies of KIF14 knockdown 8 , 10 , 15 , 16 , 19 , 20 , 35 , (partial) loss of Kif14 would be likely to reduce tumour growth. However, such loss-of-function experiments in vivo would require conditional knockouts to bypass the early postnatal lethality seen in constitutive Kif14 knockouts 26 and severe CNS phenotypes seen in humans with KIF14 mutations 27 – 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, KIF14 loss-of-function mutations in humans have been associated with an embryonic lethal phenotype of microcephaly, renal cystic dysplasia, and genitourinary and brain malformations, traits characteristic of a ciliopathy 27 . More recently, causative KIF14 mutations have been documented in patients with less severe, non-lethal microcephaly phenotypes 28 , 29 . This role in microcephaly has been touted as a potential reason to consider KIF14 as a therapeutic target for CNS malignancies 30 .…”

Section: Introductionmentioning

confidence: 99%

Observations on spontaneous tumor formation in mice overexpressing mitotic kinesin Kif14

Sishtla

Pitt

Shadmand

et al. 2018

Sci Rep

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The KIF14 locus is gained and overexpressed in various malignancies, with prognostic relevance. Its protein product, a mitotic kinesin, accelerates growth of normal mammary epithelial cells in vitro and retinoblastoma tumours in a mouse model, while KIF14 knockdown blocks growth of brain, liver, ovarian, breast, prostate, and other tumour cells and xenografts. However, the tumour-initiating effects of Kif14 overexpression have not been studied. We aged a cohort of Kif14-overexpressing transgenic mice and wild-type littermates and documented survival, cause of death, and tumour burden. The Kif14 transgene was expressed in all tissues examined, and was associated with increased proliferation marker expression. Neither mouse weights nor overall survival differed between genotypes. However, Kif14 transgenic mice showed a higher incidence of fatal lymphomas (73 vs. 50%, p = 0.03, Fisher’s exact test), primarily follicular and diffuse B-cell lymphomas. Non-tumour findings included a bilateral ballooning degeneration of lens in 12% of Kif14 transgenic mice but no wild-type mice (p = 0.02). Overall, this work reveals a novel association of Kif14 overexpression with lymphoma but suggests that Kif14 does not have as prominent a role in initiating cancer in other cell types as it does in accelerating tumour development in response to other oncogenic insults.

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“…Invalidation of KIF14 in rodents leads to severe microcephaly and growth retardation but no ciliopathy‐like phenotypes [Fujikura et al ., ]. In humans, biallelic recessive mutations in KIF14 [Moawia et al ., ; Makrythanasis et al ., ] were recently identified in individuals with mild to very severe microcephaly. The pathogenic effects of the mutations were thought to be linked to the major role of KIF14 at the midbody and to impaired cytokinesis.…”

Section: Pc‐specific Kifmentioning

confidence: 99%

Ciliary kinesins beyond IFT: Cilium length, disassembly, cargo transport and signalling

Reilly

Benmerah

2019

Biology of the Cell

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Cilia and flagella are microtubule-based antenna which are highly conserved among eukaryotes. In vertebrates, primary and motile cilia have evolved to exert several key functions during development and tissue homoeostasis. Ciliary dysfunction in humans causes a highly heterogeneous group of diseases called ciliopathies, a class of genetic multisystemic disorders primarily affecting kidney, skeleton, retina, lung and the central nervous system. Among key ciliary proteins, kinesin family members (KIF) are microtubule-interacting proteins involved in many diverse cellular functions, including transport of cargo (organelles, proteins and lipids) along microtubules and regulating the dynamics of cytoplasmic and spindle microtubules through their depolymerising activity. Many KIFs are also involved in diverse ciliary functions including assembly/disassembly, motility and signalling. We here review these ciliary kinesins in vertebrates and focus on their involvement in ciliopathy-related disorders.

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Biallelic variants in KIF14 cause intellectual disability with microcephaly

Cited by 52 publications

References 37 publications

KIF14 promotes cell proliferation via activation of Akt and is directly targeted by miR-200c in colorectal cancer

KIF14 promotes cell proliferation via activation of Akt and is directly targeted by miR-200c in colorectal cancer

Observations on spontaneous tumor formation in mice overexpressing mitotic kinesin Kif14

Ciliary kinesins beyond IFT: Cilium length, disassembly, cargo transport and signalling

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