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-AgostoHane 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

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)


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.Gln77Lys11], c.399_400del [p.Glu133Aspfs37], 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 languageEnglish
Pages (from-to)1330-1341
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number7
Publication statusPublished - 1 Jul 2021

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Published by Elsevier Inc.


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