De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy PMID: 34102099

ADC Targets in Oncology

2026-04-10

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

Am J Hum Genet. 2021 Jul 1;108(7):1330-1341. doi: 10.1016/j.ajhg.2021.05.007.

Muhammad A Usmani ¹ , Zubair M Ahmed ² , Pamela Magini ³ , Victor Murcia Pienkowski ⁴ , Kristen J Rasmussen ⁵ , Rebecca Hernan ⁶ , Faiza Rasheed ⁷ , Mureed Hussain ⁸ , Mohsin Shahzad ⁹ , Brendan C Lanpher ⁵ , Zhiyv Niu ¹⁰ , Foong-Yen Lim ¹¹ , Tommaso Pippucci ³ , Rafal Ploski ⁴ , Verena Kraus ¹² , Karolina Matuszewska ¹³ , Flavia Palombo ¹⁴ , Jessica Kianmahd ¹⁵ , UCLA Clinical Genomics Center , Julian A Martinez-Agosto ¹⁶ , Hane Lee ¹⁷ , Emma Colao ¹⁸ , M Mahdi Motazacker ¹⁹ , Karlla W Brigatti ²⁰ , Erik G Puffenberger ²⁰ , S Amer Riazuddin ²¹ , Claudia Gonzaga-Jauregui ²² , Wendy K Chung ²³ , Matias Wagner ²⁴ , Matthew J Schultz ⁵ , Marco Seri ²⁵ , Anneke J A Kievit ²⁶ , Nicola Perrotti ²⁷ , J S Klein Wassink-Ruiter ²⁸ , Hans van Bokhoven ²⁹ , Sheikh Riazuddin ³⁰ , Saima Riazuddin ³¹

Affiliations

1. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan.
2. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Molecular Biology and Biochemistry, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
3. U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy.
4. Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland.
5. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
6. Department of Pediatrics, Columbia University, New York, NY 10032, USA.
7. Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
8. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
9. Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan.
10. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
11. Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
12. Department of Pediatrics, Klinik für Kinder- und Jugendmedizin, München Klinik Schwabing und Harlaching, Klinikum Rechts der Isar der Technischen Universität Munich, Munich, Germany.
13. Department of Medical Genetics, University of Medical Sciences, 60-806 Poznan, Poland; Centers for Medical Genetics GENESIS, Grudzieniec, 60-406 Poznan, Poland.
14. U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy.
15. Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
16. Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
17. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
18. Medical Genetics Unit, Mater Domini University Hospital, 88100 Catanzaro, Italy.
19. Amsterdam Laboratory of Genome Diagnostics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
20. Clinic for Special Children, Strasburg, PA 17579, USA.
21. The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
22. Regeneron Genetics Center, Tarrytown, NY 10591, USA.
23. Department of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA.
24. Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
25. U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy; Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy.
26. Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, the Netherlands.
27. Department of Health Sciences, University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy.
28. Department of Genetics, University of Groningen, University Medical Center Groningen, P.O. box 30.001, 9700 RB Groningen, the Netherlands.
29. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. box 9101, 6500 HB Nijmegen, the Netherlands.
30. Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
31. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Molecular Biology and Biochemistry, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. Electronic address: [email protected].

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.

Keywords

AP-1 complex; AP1G1; Pakistani families; developmental delay; epilepsy; exome sequencing; genetic heterogeneity; intellectual disabilities; neurodevelopment disorder.