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Your search keyword '"Megahed, Hisham"' showing total 3 results
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3 results on '"Megahed, Hisham"'

1. Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.

Author

Schaffer AE, Breuss MW, Caglayan AO, Al-Sanaa N, Al-Abdulwahed HY, Kaymakçalan H, Yılmaz C, Zaki MS, Rosti RO, Copeland B, Baek ST, Musaev D, Scott EC, Ben-Omran T, Kariminejad A, Kayserili H, Mojahedi F, Kara M, Cai N, Silhavy JL, Elsharif S, Fenercioglu E, Barshop BA, Kara B, Wang R, Stanley V, James KN, Nachnani R, Kalur A, Megahed H, Incecik F, Danda S, Alanay Y, Faqeih E, Melikishvili G, Mansour L, Miller I, Sukhudyan B, Chelly J, Dobyns WB, Bilguvar K, Jamra RA, Gunel M, and Gleeson JG

Subjects
Actin-Related Protein 2-3 Complex metabolism, Animals, Cerebral Cortex metabolism, Cerebral Cortex pathology, Embryo, Mammalian, Genome, Human, Humans, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins genetics, Neurons metabolism, Pedigree, alpha Catenin metabolism, Actin-Related Protein 2-3 Complex genetics, Cell Movement genetics, Cerebral Cortex physiology, Neurons pathology, alpha Catenin genetics
Abstract

Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities 1 . Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.

Published
2018
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2. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

Author

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, and Gleeson JG

Subjects
Animals, Axons physiology, Biological Transport genetics, Cohort Studies, Gene Regulatory Networks, Humans, Mutation, Nucleotides genetics, Nucleotides metabolism, Sequence Analysis, DNA, Synapses physiology, Transcriptome, Zebrafish, Exome genetics, Genetic Association Studies, Motor Neuron Disease genetics, Neurons metabolism, Pyramidal Tracts metabolism, Spastic Paraplegia, Hereditary genetics
Abstract

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

Published
2014
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3. Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration

Author

Schaffer, Ashleigh E, Breuss, Martin W, Caglayan, Ahmet Okay, Al-Sanaa, Nouriya, Al-Abdulwahed, Hind Y, Kaymakçalan, Hande, Yılmaz, Cahide, Zaki, Maha S, Rosti, Rasim O, Copeland, Brett, Baek, Seung Tae, Musaev, Damir, Scott, Eric C, Ben-Omran, Tawfeg, Kariminejad, Ariana, Kayserili, Hulya, Mojahedi, Faezeh, Kara, Majdi, Cai, Na, Silhavy, Jennifer L, Elsharif, Seham, Fenercioglu, Elif, Barshop, Bruce A, Kara, Bulent, Wang, Rengang, Stanley, Valentina, James, Kiely N, Nachnani, Rahul, Kalur, Aneesha, Megahed, Hisham, Incecik, Faruk, Danda, Sumita, Alanay, Yasemin, Faqeih, Eissa, Melikishvili, Gia, Mansour, Lobna, Miller, Ian, Sukhudyan, Biayna, Chelly, Jamel, Dobyns, William B, Bilguvar, Kaya, Jamra, Rami Abou, Gunel, Murat, and Gleeson, Joseph G

Subjects
Cerebral Cortex, Neurons, Genome, Mammalian, Neurosciences, Nerve Tissue Proteins, macromolecular substances, Biological Sciences, Inbred C57BL, Medical and Health Sciences, Actin-Related Protein 2-3 Complex, Pedigree, Mice, Rare Diseases, Cell Movement, Embryo, Clinical Research, Mutation, Neurological, Animals, Humans, 2.1 Biological and endogenous factors, alpha Catenin, Human, Developmental Biology
Abstract

Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.

Published
2018

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