Genomic and phenotypic delineation of congenital microcephaly

Shaheen, Ranad; Maddirevula, Sateesh; Ewida, Nour; Alsahli, Saud; Abdel-Salam, Ghada M.H.; Zaki, Maha S.; Tala, Saeed Al; Alhashem, Amal; Softah, Ameen; Al‐Owain, Mohammed; Alazami, Anas M.; Abadel, Basma; Patel, Nisha; Al‐Sheddi, Tarfa; Alomar, Rana; Alobeid, Eman; Ibrahim, Niema; Abdulwahab, Firdous; Hamad, Muddathir H.; Tabarki, Brahim; Alwadei, Ali H; Al-Hazzani, Fahad; Bashiri, Fahad A.; Kentab, Amal Y.; Şahintürk, Serdar; Sherr, Elliott H.; Fregeau, Brieana; Sogati, Samira; AlShahwan, Saad; Alkhalifi, Salwa; Al-Humaidi, Zainab; Temtamy, Samia A.; Aglan, Mona; Otaify, Ghada A.; Girisha, Katta M.; Tulbah, Maha; Seidahmed, Mohammed Zain; Salih, Mustafa A.; Abouelhoda, Mohamed; Momin, Afaque Ahmad Imtiyaz; Saffar, Muna Al; Partlow, Jennifer N.; Arold, Stefan T.; Faqeih, Eissa; Walsh, Christopher A.; Alkuraya, Fowzan S.

doi:10.1038/s41436-018-0140-3

Cited by 93 publications

(116 citation statements)

References 39 publications

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“…Comparing the flavivirus-human networks, we identified several such ZIKV-specific interactions (Figure S4), including a connection between NS4A and ANKLE2. Interestingly, ANKLE2 mutations cause an autosomal recessive microcephaly in humans (Shaheen et al, 2018; Yamamoto et al, 2014). These effects are conserved in Drosophila , a well-established model organism for brain development (Wangler et al, 2015), as fly Ankle2 hypomorphic mutants ( Ankle2 A ) are pupal lethal and exhibit microcephaly.…”

Section: Resultsmentioning

confidence: 99%

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Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Shah

Link

Jang

et al. 2018

Cell

266

355

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Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provide information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C, and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights, and when coupled with in vivo models, can be used to unravel pathogenic mechanisms.

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Section: Resultsmentioning

confidence: 99%

“…Of all ZIKV targets identified in our proteomic approach, only ANKLE2 was previously linked to severe microcephaly (Shaheen et al, 2018; Yamamoto et al, 2014). In addition, ANKLE2-associated phenotypes are strikingly similar to ZIKV-associated microcephaly (Moore et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Shah

Link

Jang

et al. 2018

Cell

266

355

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“…Three families were found to fulfill these criteria in probands with neurologically associated phenotypes ( Figure 1D and S1, Table S2). These cases suggest that a diverse set of variants in ANKLE2 may be associated with a spectrum of neurologic disease (Figure 1) and reveal either sporadic disease, apparent vertical transmission, and in some cases, consanguineous parentage (Yamamoto et al, 2014;Shaheen et al, 2018); (Figure S1). The identified mutations are missense, nonsense, or splicing variants that lead to premature stop codons; all subjects have biallelic variants, either compound heterozygous or homozygous alleles (Figure 1 and S1).…”

Section: Human Ankle2 Variants Cause Microcephalymentioning

confidence: 99%

“…Ten families have been described with biallelic variants in VRK1 that cause a spectrum of neurologic diseases including 6 individuals with microcephaly (Feng et al, 2018;Gonzaga-Jauregui et al, 2013;Najmabadi et al, 2011;Nguyen et al, 2015;Renbaum et al, 2009;Shaheen et al, 2018;Stoll et al, 2016) (Table S1; Figure S5). The family structures suggest either a sporadic or recessive neurological disease trait; historical consanguinity in 3/10 pedigrees implicate an autosomal recessive locus.…”

Section: Disease Associated Variants In Vrk1 and Its Paralogsmentioning

confidence: 99%

“…It is associated with neurodevelopmental disorders, such as developmental delay and intellectual disability (DD/ID) and can be caused by external exposures to toxins, in utero infections, or gene mutations. Pathogenic gene variants for microcephaly have been identified through targeted genetic testing, genomic copy number studies, and exome sequencing (ES) (Brunetti-Pierri et al, 2008;Dumas et al, 2012;Lupski, 2015;Shinawi et al, 2010;Shaheen et al, 2018), elucidating about 18 primary microcephaly loci. Many syndromes significantly overlap with classic microcephaly phenotypes, and together, these disorders can be caused by defects in a wide variety of biological processes, including centriole biogenesis, DNA replication, DNA repair, cell cycle and cytokinesis, genome stability, as well as multiple cell signaling pathways (Jayaraman, Bae and Walsh, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Ankle2, A Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

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Chung

Jolly

et al. 2019

Preprint

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words)Neuroblasts in flies divide asymmetrically by establishing polarity, distributing cell fate determinants asymmetrically, and positioning their spindle for cell division. The apical complex contains aPKC, Bazooka (Par3), and Par6, and its activity depends on L(2)gl. We show that Ankle2 interacts with L(2)gl and affects aPKC. Reducing Ankle2 levels disrupts ER and nuclear envelope morphology, releasing the kinase Ballchen/VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen/VRK1 or l(2)gl suppresses the loss of Ankle2 and restores viability and brain size. The Zika virus NS4A protein 3 interacts with Drosophila Ankle2 and VRK1 in dividing neuroblasts. Human mutational studies implicate this neural cell division pathway in microcephaly and motor neuron disease. In summary, NS4A, ANKLE2, VRK1 and LLGL1 define a novel pathway that impinges on asymmetric determinants of neural stem cell division.However, all experiments in worms were performed at the embryonic two-cell stage, and no other phenotypes were reported except early lethality. Whilst mutations in ANKLE2 have been associated with severe microcephaly (OFC z-sore = -2.5 to -9), human VRK1 pathogenic variant alleles can cause a neurological disease trait consisting of complex motor and sensory axonal neuropathy and microcephaly .Mutations in both Ankle2 and the fly homologue of VRK1, ballchen, cause a loss of neuroblasts in 3 rd instar larval brains in Drosophila (Yamamoto et al., 2014;Yakulov et al., 2014). Neuroblasts (NBs) divide asymmetrically and are often used as a model to investigate stem cell biology (Homem and Knoblich, 2012) and asymmetric cell division (Gallaud et al., 2017). Most NBs in the larval central brain give rise to another NB and a smaller ganglion mother cell (GMC), which then divides once again to produce neurons or glia. Proper NB maintenance and regulation is essential for precise development of the adult nervous system, and misregulation of NB number or function can lead to defects in brain size (Wang et al., 2009;Gateff and Schneiderman, 1974).Congenital Zika infection in humans during pregnancy has been associated with severe microcephaly that can be as dramatic as certain genetic forms of microcephaly including phenotypes associated with bi-allelic mutations in MCPH16/ANKLE2 (Moore et al., 2017;Yamamoto et al., 2014). Recently, we showed that a Zika protein, NS4A, physically interacts with ANKLE2 in human cells. Expression of NS4A in larval brains causes microcephaly, induces apoptosis, and reduces proliferation. Importantly, expression of human ANKLE2 in flies that express NS4A suppresses the associated phenotypes, demonstrating that NS4A interacts with the ANKLE2 protein and inhibits its function (Shah et al., 2018). Interestingly, the Zika virus crosses the blood brain barrier and targets radial glial cells, the neural progenitors in the vertebrate cortex (Devhare et al., 20...

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Genetic Counseling: Preconception, Prenatal, and Perinatal

Milunsky

2021

Genetic Disorders and the Fetus

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Genomic and phenotypic delineation of congenital microcephaly

Abstract: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Cited by 93 publications

References 39 publications

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Ankle2, A Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

Genetic Counseling: Preconception, Prenatal, and Perinatal

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