Mutations of <i>KIF14</i> cause primary microcephaly by impairing cytokinesis

Moawia, Abubakar; Shaheen, Ranad; Rasool, Sajida; Waseem, Syeda Seema; Ewida, Nour; Budde, Birgit; Kawalia, Amit; Motameny, Susanne; Khan, Kamal; Fatima, Ambrin; Jameel, Muhammad; Ullah, Farid; Akram, Talia; Ali, Zafar; Abdullah, Uzma; Irshad, Saba; Höhne, Wolfgang; Noegel, Angelika A.; Al‐Owain, Mohammed; Hörtnagel, Konstanze; Stöbe, Petra; Baig, Shahid Mahmood; Nürnberg, Peter; Alkuraya, Fowzan S.; Hahn, Andreas; Hussain, Muhammad Sajid

doi:10.1002/ana.25044

Cited by 68 publications

(57 citation statements)

References 35 publications

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“…The authors found that cerebral and cerebellar hypoplasia were a result of increased apoptosis and reduced proliferation during embryogenesis. Recently, KIF14 mutation was identified as the driver of a form of primary, autosomal recessive microcephaly in four families [53] . These independent families were from Pakistan, Saudi Arabia, and Germany, and encompassed a total of ten individuals with microcephaly and homozygous and compound heterozygous KIF14 mutations that resulted in aberrant splicing or truncated protein.…”

Section: Kif14 Is Mutated In Primary Microcephaly and Upregulated mentioning

confidence: 99%

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

Lang

Gershon

2018

BioEssays

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New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity.

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Section: Kif14 Is Mutated In Primary Microcephaly and Upregulated mentioning

confidence: 99%

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

Lang

Gershon

2018

BioEssays

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“…The polarized form of cytokinesis in embryonic cortical NSCs is poorly understood, but may influence the segregation of organelles and apical fate determinants to daughter cells as they make fate choices. Recent findings that mutations in Kif20b and other midbody genes cause microcephaly in humans and mice suggest that brain development is especially sensitive to defects in cytokinesis (26,(35)(36)(37)(38)(39). To elucidate these issues, we developed methods to quantitatively analyze furrowing and abscission in NSCs of the developing cerebral cortex.…”

Section: Discussionmentioning

confidence: 99%

Cytokinetic furrowing and abscission dynamics during brain development revealed by live imaging

McNeely

Little²,

Dwyer

2019

Preprint

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Building a brain of the proper size and structure requires neural stem cells (NSCs) to divide with tight temporal and spatial control to produce different daughter cell types in proper numbers and sequence. Mammalian NSCs in the embryonic cortex must maintain their polarized epithelial structure as they undergo both early proliferative divisions and later neurogenic divisions. To do this they undergo a polarized form of cytokinesis at the apical membrane that is not well understood. Here we investigate whether polarized furrowing and abscission in mouse NSCs are regulated differently at earlier and later stages, and in a cytokinesis mutant, Kif20b. We developed methods to live image furrow ingression and midbody microtubule abscission in NSCs within cortical explants. We find that polarized furrow ingression occurs at a steady rate and completes in 15 minutes, regardless of developmental age. However, ingression is slowed in a subset of Kif20b mutant NSCs. Abscission is usually observed on both midbody flanks, and takes 65-75 minutes to complete. Surprisingly, the process is accelerated in the microcephalic Kif20b mutant NSCs. Midbody remnants litter the apical membrane surface, and are more prevalent with early proliferative divisions. These results suggest that abscission is developmentally regulated in NSCs and may influence proper brain growth and structure.

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“…MCPH1 encodes 835 amino‐acid protein with reported roles at least in DDR, cell cycle control and maintenance of chromosomal integrity . Curiously, MCPH1 has also been identified as causative gene for primary microcephaly (OMIM #251200), a neurodevelopmental disorder defined by marked reduction in brain size, mental retardation and short stature . At cellular level, the key phenotype seen in these patients is premature chromosome condensation (PCC) .…”

Section: Introductionmentioning

confidence: 99%

“…5,7 Curiously, MCPH1 has also been identified as causative gene for primary microcephaly (OMIM #251200), a neurodevelopmental disorder defined by marked reduction in brain size, mental retardation and short stature. 8,9 At cellular level, the key phenotype seen in these patients is premature chromosome condensation (PCC). 10,11 During DDR, MCPH1 is also involved in the regulation of chromatin condensation status, as it is required to recruit and maintain ATP-dependent chromatin remodeling complex SWI/SNF at the sites of DNA lesion.…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

Tervasmäki

Mantere

Eshraghi

et al. 2019

Intl Journal of Cancer

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Strong inherited predisposition to breast cancer is estimated to cause about 5–10% of all breast cancer cases. As the known susceptibility genes, such as BRCA1 and BRCA2, explain only a fraction of this, additional predisposing genes and related biological mechanisms are actively being searched for. We have recently identified a recurrent MCPH1 germline mutation, p.Arg304ValfsTer3, as a breast cancer susceptibility allele. MCPH1 encodes a multifunctional protein involved in maintenance of genomic integrity and it is also somatically altered in various cancer types, including breast cancer. Additionally, biallelic MCPH1 mutations are causative for microcephaly and at cellular level premature chromosome condensation. To study the molecular mechanisms leading to cancer predisposition and malignant conversion, here we have modeled the effect of MCPH1 p.Arg304ValfsTer3 mutation using gene‐edited MCF10A breast epithelial cells. As a complementary approach, we also sought for additional potential cancer driver mutations in MCPH1 p.Arg304ValfsTer3 carrier breast tumors. We show that mutated MCPH1 de‐regulates transcriptional programs related to invasion and metastasis and leads to downregulation of histone genes. These global transcriptional changes are mirrored by significantly increased migration and invasion potential of the cells as well as abnormal chromosomal condensation both before and after mitosis. These findings provide novel molecular insights to MCPH1 tumor suppressor functions and establish a role in regulation of transcriptional programs related to malignant conversion and chromosomal assembly. The MCPH1 p.Arg304ValfsTer3 carrier breast tumors showed recurrent tumor suppressor gene TP53 mutations, which were also significantly over‐represented in breast tumors with somatically inactivated MCPH1.

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Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Abstract: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.

Cited by 68 publications

References 35 publications

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

Cytokinetic furrowing and abscission dynamics during brain development revealed by live imaging

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

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