De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

Muhammad A. Usmani; Zubair M. Ahmed; UCLA Clinical Genomics Center; Pamela Magini; Victor Murcia Pienkowski; Kristen J. Rasmussen; Rebecca Hernan; Faiza Rasheed; Mureed Hussain; Mohsin Shahzad; Brendan C. Lanpher; Zhiyv Niu; Foong Yen Lim; Tommaso Pippucci; Rafal Ploski; Verena Kraus; Karolina Matuszewska; Flavia Palombo; Jessica Kianmahd; Julian A. Martinez-Agosto; Hane Lee; Emma Colao; M. Mahdi Motazacker; Karlla W. Brigatti; Erik G. Puffenberger; S. Amer Riazuddin; Claudia Gonzaga-Jauregui; Wendy K. Chung; Matias Wagner; Matthew J. Schultz; Marco Seri; Anneke J.A. Kievit; Nicola Perrotti; J. S.Klein Wassink-Ruiter; Hans van Bokhoven; Sheikh Riazuddin; Saima Riazuddin

doi:10.1016/j.ajhg.2021.05.007

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

Muhammad A. Usmani
, Zubair M. Ahmed
, UCLA Clinical Genomics Center
, Pamela Magini
, Victor Murcia Pienkowski
, Kristen J. Rasmussen
, Rebecca Hernan
, Faiza Rasheed
, Mureed Hussain
, Mohsin Shahzad
, Brendan C. Lanpher
, Zhiyv Niu
, Foong Yen Lim
, Tommaso Pippucci
, Rafal Ploski
, Verena Kraus
, Karolina Matuszewska
, Flavia Palombo
, Jessica Kianmahd
, Julian A. Martinez-Agosto

Hane Lee, Emma Colao, M. Mahdi Motazacker, Karlla W. Brigatti, Erik G. Puffenberger, S. Amer Riazuddin, Claudia Gonzaga-Jauregui, Wendy K. Chung, Matias Wagner, Matthew J. Schultz, Marco Seri, Anneke J.A. Kievit, Nicola Perrotti, J. S.Klein Wassink-Ruiter, Hans van Bokhoven, Sheikh Riazuddin, Saima Riazuddin^*

^*Corresponding author for this work

Clinical Genetics

University of Maryland School of Medicine
Shaheed Zulfiqar Ali Bhutto Medical University
Medical University of Warsaw
Mayo Clinic Rochester, MN
Columbia University
University of the Punjab
Cincinnati Children's Hospital Medical Center
Klinikum rechts der Isar der Technischen Universität München
University of Medical Sciences Poznan
Centers for Medical Genetics GENESIS
IRCCS Istituto delle Scienze Neurologiche di Bologna
David Geffen School of Medicine
Mater Domini University Hospital
Amsterdam UMC
Clinic for Special Children
Johns Hopkins School of Medicine
Regeneron Genetics Center
Magna Græcia University
University Medical Centre Groningen
Donders Institute for Brain, Cognition and Behaviour
University of Health Sciences Lahore
Helmholtz Zentrum München - German Research Center for Environmental Health
IRCCS Azienda Ospedaliero-Universitaria di Bologna

Research output: Contribution to journal › Article › Academic › peer-review

24 Citations (Scopus)

Abstract

Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys^∗11], c.399_400del [p.Glu133Aspfs^∗37], c.747G>T [p.Gln249His], c.928−2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.

Original language	English
Pages (from-to)	1330-1341
Number of pages	12
Journal	American Journal of Human Genetics
Volume	108
Issue number	7
DOIs	https://doi.org/10.1016/j.ajhg.2021.05.007
Publication status	Published - 1 Jul 2021

Bibliographical note

Published by Elsevier Inc.

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10.1016/j.ajhg.2021.05.007

http://www.cell.com/article/S0002929721001919/pdf

Cite this

Usmani, M. A., Ahmed, Z. M., UCLA Clinical Genomics Center, Magini, P., Pienkowski, V. M., Rasmussen, K. J., Hernan, R., Rasheed, F., Hussain, M., Shahzad, M., Lanpher, B. C., Niu, Z., Lim, F. Y., Pippucci, T., Ploski, R., Kraus, V., Matuszewska, K., Palombo, F., Kianmahd, J., ... Riazuddin, S. (2021). De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy. American Journal of Human Genetics, 108(7), 1330-1341. https://doi.org/10.1016/j.ajhg.2021.05.007

@article{09c89b89546641f2bcbb8dacee99b176,

title = "De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy",

abstract = "Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399\_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928−2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.",

author = "Usmani, \{Muhammad A.\} and Ahmed, \{Zubair M.\} and \{UCLA Clinical Genomics Center\} and Pamela Magini and Pienkowski, \{Victor Murcia\} and Rasmussen, \{Kristen J.\} and Rebecca Hernan and Faiza Rasheed and Mureed Hussain and Mohsin Shahzad and Lanpher, \{Brendan C.\} and Zhiyv Niu and Lim, \{Foong Yen\} and Tommaso Pippucci and Rafal Ploski and Verena Kraus and Karolina Matuszewska and Flavia Palombo and Jessica Kianmahd and Martinez-Agosto, \{Julian A.\} and Hane Lee and Emma Colao and Motazacker, \{M. Mahdi\} and Brigatti, \{Karlla W.\} and Puffenberger, \{Erik G.\} and Riazuddin, \{S. Amer\} and Claudia Gonzaga-Jauregui and Chung, \{Wendy K.\} and Matias Wagner and Schultz, \{Matthew J.\} and Marco Seri and Kievit, \{Anneke J.A.\} and Nicola Perrotti and Wassink-Ruiter, \{J. S.Klein\} and \{van Bokhoven\}, Hans and Sheikh Riazuddin and Saima Riazuddin",

note = "Published by Elsevier Inc.",

year = "2021",

month = jul,

day = "1",

doi = "10.1016/j.ajhg.2021.05.007",

language = "English",

volume = "108",

pages = "1330--1341",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "7",

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Usmani, MA, Ahmed, ZM, UCLA Clinical Genomics Center, Magini, P, Pienkowski, VM, Rasmussen, KJ, Hernan, R, Rasheed, F, Hussain, M, Shahzad, M, Lanpher, BC, Niu, Z, Lim, FY, Pippucci, T, Ploski, R, Kraus, V, Matuszewska, K, Palombo, F, Kianmahd, J, Martinez-Agosto, JA, Lee, H, Colao, E, Motazacker, MM, Brigatti, KW, Puffenberger, EG, Riazuddin, SA, Gonzaga-Jauregui, C, Chung, WK, Wagner, M, Schultz, MJ, Seri, M, Kievit, AJA, Perrotti, N, Wassink-Ruiter, JSK, van Bokhoven, H, Riazuddin, S & Riazuddin, S 2021, 'De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy', American Journal of Human Genetics, vol. 108, no. 7, pp. 1330-1341. https://doi.org/10.1016/j.ajhg.2021.05.007

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy. / Usmani, Muhammad A.; Ahmed, Zubair M.; UCLA Clinical Genomics Center et al.
In: American Journal of Human Genetics, Vol. 108, No. 7, 01.07.2021, p. 1330-1341.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

AU - Usmani, Muhammad A.

AU - Ahmed, Zubair M.

AU - UCLA Clinical Genomics Center

AU - Magini, Pamela

AU - Pienkowski, Victor Murcia

AU - Rasmussen, Kristen J.

AU - Hernan, Rebecca

AU - Rasheed, Faiza

AU - Hussain, Mureed

AU - Shahzad, Mohsin

AU - Lanpher, Brendan C.

AU - Niu, Zhiyv

AU - Lim, Foong Yen

AU - Pippucci, Tommaso

AU - Ploski, Rafal

AU - Kraus, Verena

AU - Matuszewska, Karolina

AU - Palombo, Flavia

AU - Kianmahd, Jessica

AU - Martinez-Agosto, Julian A.

AU - Lee, Hane

AU - Colao, Emma

AU - Motazacker, M. Mahdi

AU - Brigatti, Karlla W.

AU - Puffenberger, Erik G.

AU - Riazuddin, S. Amer

AU - Gonzaga-Jauregui, Claudia

AU - Chung, Wendy K.

AU - Wagner, Matias

AU - Schultz, Matthew J.

AU - Seri, Marco

AU - Kievit, Anneke J.A.

AU - Perrotti, Nicola

AU - Wassink-Ruiter, J. S.Klein

AU - van Bokhoven, Hans

AU - Riazuddin, Sheikh

AU - Riazuddin, Saima

N1 - Published by Elsevier Inc.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928−2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.

AB - Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928−2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.

UR - https://www.scopus.com/pages/publications/85108892721

U2 - 10.1016/j.ajhg.2021.05.007

DO - 10.1016/j.ajhg.2021.05.007

M3 - Article

C2 - 34102099

AN - SCOPUS:85108892721

SN - 0002-9297

VL - 108

SP - 1330

EP - 1341

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 7

ER -

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

Abstract

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