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

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

doi:10.1038/s41588-018-0166-0

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

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

Research output: Contribution to journal › Letter › peer-review

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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.

Original language	English (US)
Pages (from-to)	1093-1101
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	8
DOIs	https://doi.org/10.1038/s41588-018-0166-0
State	Published - Aug 1 2018
Externally published	Yes

Bibliographical note

Funding Information:
We thank the patients and their families for participation. We thank A. Wynshaw-Boris for generous scientific and editorial input. The research was supported by NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, Qatar National Research Fund number 6-1463-351, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G). A.E.S. is a recipient of an A.P. Giannini Fellowship and an NIH Pathway to Independence Award, R00HD082337. S.T.B. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. We thank the Broad Institute and Yale Center for Mendelian Disorders (UMIHG008900 to D. MacArthur and H. Rehm, and UMIHG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G). We acknowledge M. Gerstein, S. Mane, A. B. Ekici, and S. Uebe for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics and Genomics. Exome data have been deposited into the database of Genotypes and Phenotypes (phs000288).

Publisher Copyright:
© 2018, The Author(s).

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Schaffer, A. E., Breuss, M. W., Caglayan, A. O., Al-Sanaa, N., Al-Abdulwahed, H. Y., Kaymakçalan, H., Yılmaz, C., Zaki, M. S., Rosti, R. O., Copeland, B., Baek, S. T., Musaev, D., Scott, E. C., Ben-Omran, T., Kariminejad, A., Kayserili, H., Mojahedi, F., Kara, M., Cai, N., ... Gleeson, J. G. (2018). Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration. Nature Genetics, 50(8), 1093-1101. https://doi.org/10.1038/s41588-018-0166-0

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 & Gleeson, JG 2018, 'Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration', Nature Genetics, vol. 50, no. 8, pp. 1093-1101. https://doi.org/10.1038/s41588-018-0166-0

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

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.",

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

note = "Funding Information: We thank the patients and their families for participation. We thank A. Wynshaw-Boris for generous scientific and editorial input. The research was supported by NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, Qatar National Research Fund number 6-1463-351, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G). A.E.S. is a recipient of an A.P. Giannini Fellowship and an NIH Pathway to Independence Award, R00HD082337. S.T.B. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. We thank the Broad Institute and Yale Center for Mendelian Disorders (UMIHG008900 to D. MacArthur and H. Rehm, and UMIHG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G). We acknowledge M. Gerstein, S. Mane, A. B. Ekici, and S. Uebe for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics and Genomics. Exome data have been deposited into the database of Genotypes and Phenotypes (phs000288). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = aug,

day = "1",

doi = "10.1038/s41588-018-0166-0",

language = "English (US)",

volume = "50",

pages = "1093--1101",

journal = "Nature Genetics",

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TY - JOUR

T1 - Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration

AU - Schaffer, Ashleigh E.

AU - Breuss, Martin W.

AU - Caglayan, Ahmet Okay

AU - Al-Sanaa, Nouriya

AU - Al-Abdulwahed, Hind Y.

AU - Kaymakçalan, Hande

AU - Yılmaz, Cahide

AU - Zaki, Maha S.

AU - Rosti, Rasim O.

AU - Copeland, Brett

AU - Baek, Seung Tae

AU - Musaev, Damir

AU - Scott, Eric C.

AU - Ben-Omran, Tawfeg

AU - Kariminejad, Ariana

AU - Kayserili, Hulya

AU - Mojahedi, Faezeh

AU - Kara, Majdi

AU - Cai, Na

AU - Silhavy, Jennifer L.

AU - Elsharif, Seham

AU - Fenercioglu, Elif

AU - Barshop, Bruce A.

AU - Kara, Bulent

AU - Wang, Rengang

AU - Stanley, Valentina

AU - James, Kiely N.

AU - Nachnani, Rahul

AU - Kalur, Aneesha

AU - Megahed, Hisham

AU - Incecik, Faruk

AU - Danda, Sumita

AU - Alanay, Yasemin

AU - Faqeih, Eissa

AU - Melikishvili, Gia

AU - Mansour, Lobna

AU - Miller, Ian

AU - Sukhudyan, Biayna

AU - Chelly, Jamel

AU - Dobyns, William B.

AU - Bilguvar, Kaya

AU - Jamra, Rami Abou

AU - Gunel, Murat

AU - Gleeson, Joseph G.

N1 - Funding Information: We thank the patients and their families for participation. We thank A. Wynshaw-Boris for generous scientific and editorial input. The research was supported by NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, Qatar National Research Fund number 6-1463-351, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G). A.E.S. is a recipient of an A.P. Giannini Fellowship and an NIH Pathway to Independence Award, R00HD082337. S.T.B. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. We thank the Broad Institute and Yale Center for Mendelian Disorders (UMIHG008900 to D. MacArthur and H. Rehm, and UMIHG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G). We acknowledge M. Gerstein, S. Mane, A. B. Ekici, and S. Uebe for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics and Genomics. Exome data have been deposited into the database of Genotypes and Phenotypes (phs000288). Publisher Copyright: © 2018, The Author(s).

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

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M3 - Letter

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EP - 1101

JO - Nature Genetics

JF - Nature Genetics

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ER -

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

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