Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish

Victoria Patterson; Farid Ullah; Laura Bryant; John N. Griffin; Alpa Sidhu; Sheila Saliganan; Mackenzie Blaile; Margarita S. Saenz; Rosemarie Smith; Sara Ellingwood; Dorothy K. Grange; Xuyun Hu; Maimaiti Mireguli; Yanfei Luo; Yiping Shen; Maureen Mulhern; Elaine Zackai; Alyssa Ritter; Kosaki Izumi; Julia Hoefele; Matias Wagner; Korbinian M. Riedhammer; Barbara Seitz; Nathaniel H. Robin; Dana Goodloe; Cyril Mignot; Boris Keren; Helen Cox; Joanna Jarvis; Maja Hempel; Cynthia Forster Gibson; Frederic Tran Mau-Them; Antonio Vitobello; Ange Line Bruel; Arthur Sorlin; Sarju Mehta; F. Lucy Raymond; Kelly Gilmore; Bradford C. Powell; Karen Weck; Chumei Li; Anneke T. Vulto-Van Silfhout; Thea Giacomini; Maria Margherita Mancardi; Andrea Accogli; Vincenzo Salpietro; Federico Zara; Neeta L. Vora; Erica E. Davis; Rebecca Burdine; Elizabeth Bhoj

doi:10.1126/sciadv.ade0631

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish

Victoria Patterson, Farid Ullah, Laura Bryant, John N. Griffin, Alpa Sidhu, Sheila Saliganan, Mackenzie Blaile, Margarita S. Saenz, Rosemarie Smith, Sara Ellingwood, Dorothy K. Grange, Xuyun Hu, Maimaiti Mireguli, Yanfei Luo, Yiping Shen, Maureen Mulhern, Elaine Zackai, Alyssa Ritter, Kosaki Izumi, Julia HoefeleMatias Wagner, Korbinian M. Riedhammer, Barbara Seitz, Nathaniel H. Robin, Dana Goodloe, Cyril Mignot, Boris Keren, Helen Cox, Joanna Jarvis, Maja Hempel, Cynthia Forster Gibson, Frederic Tran Mau-Them, Antonio Vitobello, Ange Line Bruel, Arthur Sorlin, Sarju Mehta, F. Lucy Raymond, Kelly Gilmore, Bradford C. Powell, Karen Weck, Chumei Li, Anneke T. Vulto-Van Silfhout, Thea Giacomini, Maria Margherita Mancardi, Andrea Accogli, Vincenzo Salpietro, Federico Zara, Neeta L. Vora, Erica E. Davis, Rebecca Burdine, Elizabeth Bhoj

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Abstract

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

Original language	English (US)
Article number	eade0631
Journal	Science Advances
Volume	9
Issue number	17
DOIs	https://doi.org/10.1126/sciadv.ade0631
State	Published - Apr 2023
Externally published	Yes

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Patterson, V., Ullah, F., Bryant, L., Griffin, J. N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M. S., Smith, R., Ellingwood, S., Grange, D. K., Hu, X., Mireguli, M., Luo, Y., Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., ... Bhoj, E. (2023). Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish. Science Advances, 9(17), Article eade0631. https://doi.org/10.1126/sciadv.ade0631

Patterson, V, Ullah, F, Bryant, L, Griffin, JN, Sidhu, A, Saliganan, S, Blaile, M, Saenz, MS, Smith, R, Ellingwood, S, Grange, DK, Hu, X, Mireguli, M, Luo, Y, Shen, Y, Mulhern, M, Zackai, E, Ritter, A, Izumi, K, Hoefele, J, Wagner, M, Riedhammer, KM, Seitz, B, Robin, NH, Goodloe, D, Mignot, C, Keren, B, Cox, H, Jarvis, J, Hempel, M, Gibson, CF, Mau-Them, FT, Vitobello, A, Bruel, AL, Sorlin, A, Mehta, S, Raymond, FL, Gilmore, K, Powell, BC, Weck, K, Li, C, Vulto-Van Silfhout, AT, Giacomini, T, Mancardi, MM, Accogli, A, Salpietro, V, Zara, F, Vora, NL, Davis, EE, Burdine, R & Bhoj, E 2023, 'Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish', Science Advances, vol. 9, no. 17, eade0631. https://doi.org/10.1126/sciadv.ade0631

@article{6bb1daaa649941a2b4fc893ef11db61c,

title = "Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish",

abstract = "We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.",

author = "Victoria Patterson and Farid Ullah and Laura Bryant and Griffin, {John N.} and Alpa Sidhu and Sheila Saliganan and Mackenzie Blaile and Saenz, {Margarita S.} and Rosemarie Smith and Sara Ellingwood and Grange, {Dorothy K.} and Xuyun Hu and Maimaiti Mireguli and Yanfei Luo and Yiping Shen and Maureen Mulhern and Elaine Zackai and Alyssa Ritter and Kosaki Izumi and Julia Hoefele and Matias Wagner and Riedhammer, {Korbinian M.} and Barbara Seitz and Robin, {Nathaniel H.} and Dana Goodloe and Cyril Mignot and Boris Keren and Helen Cox and Joanna Jarvis and Maja Hempel and Gibson, {Cynthia Forster} and Mau-Them, {Frederic Tran} and Antonio Vitobello and Bruel, {Ange Line} and Arthur Sorlin and Sarju Mehta and Raymond, {F. Lucy} and Kelly Gilmore and Powell, {Bradford C.} and Karen Weck and Chumei Li and {Vulto-Van Silfhout}, {Anneke T.} and Thea Giacomini and Mancardi, {Maria Margherita} and Andrea Accogli and Vincenzo Salpietro and Federico Zara and Vora, {Neeta L.} and Davis, {Erica E.} and Rebecca Burdine and Elizabeth Bhoj",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = apr,

doi = "10.1126/sciadv.ade0631",

language = "English (US)",

volume = "9",

journal = "Science Advances",

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T1 - Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish

AU - Patterson, Victoria

AU - Ullah, Farid

AU - Bryant, Laura

AU - Griffin, John N.

AU - Sidhu, Alpa

AU - Saliganan, Sheila

AU - Blaile, Mackenzie

AU - Saenz, Margarita S.

AU - Smith, Rosemarie

AU - Ellingwood, Sara

AU - Grange, Dorothy K.

AU - Hu, Xuyun

AU - Mireguli, Maimaiti

AU - Luo, Yanfei

AU - Shen, Yiping

AU - Mulhern, Maureen

AU - Zackai, Elaine

AU - Ritter, Alyssa

AU - Izumi, Kosaki

AU - Hoefele, Julia

AU - Wagner, Matias

AU - Riedhammer, Korbinian M.

AU - Seitz, Barbara

AU - Robin, Nathaniel H.

AU - Goodloe, Dana

AU - Mignot, Cyril

AU - Keren, Boris

AU - Cox, Helen

AU - Jarvis, Joanna

AU - Hempel, Maja

AU - Gibson, Cynthia Forster

AU - Mau-Them, Frederic Tran

AU - Vitobello, Antonio

AU - Bruel, Ange Line

AU - Sorlin, Arthur

AU - Mehta, Sarju

AU - Raymond, F. Lucy

AU - Gilmore, Kelly

AU - Powell, Bradford C.

AU - Weck, Karen

AU - Li, Chumei

AU - Vulto-Van Silfhout, Anneke T.

AU - Giacomini, Thea

AU - Mancardi, Maria Margherita

AU - Accogli, Andrea

AU - Salpietro, Vincenzo

AU - Zara, Federico

AU - Vora, Neeta L.

AU - Davis, Erica E.

AU - Burdine, Rebecca

AU - Bhoj, Elizabeth

PY - 2023/4

Y1 - 2023/4

N2 - We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

AB - We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

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DO - 10.1126/sciadv.ade0631

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C2 - 37126546

AN - SCOPUS:85158069250

SN - 2375-2548

VL - 9

JO - Science Advances

JF - Science Advances

IS - 17

M1 - eade0631

ER -

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish

Abstract

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