Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome

Abigail U. Carbonell, Chang Hoon Cho, Jaafar O. Tindi, Pamela A. Counts, Juliana C. Bates, Hediye Erdjument-Bromage, Svetlana Cvejic, Alana Iaboni, Ifat Kvint, Jenny Rosensaft, Ehud Banne, Evdokia Anagnostou, Thomas A. Neubert, Stephen W. Scherer, Sophie Molholm and Bryen A. Jordan ()
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Abigail U. Carbonell: Albert Einstein College of Medicine
Chang Hoon Cho: Albert Einstein College of Medicine
Jaafar O. Tindi: Albert Einstein College of Medicine
Pamela A. Counts: Albert Einstein College of Medicine
Juliana C. Bates: Albert Einstein College of Medicine
Hediye Erdjument-Bromage: New York University School of Medicine
Svetlana Cvejic: Albert Einstein College of Medicine
Alana Iaboni: Holland Bloorview Kids Rehabilitation Hospital
Ifat Kvint: Hebrew University Hadassah Medical School
Jenny Rosensaft: Hebrew University Hadassah Medical School
Ehud Banne: Hebrew University Hadassah Medical School
Evdokia Anagnostou: Holland Bloorview Kids Rehabilitation Hospital
Thomas A. Neubert: New York University School of Medicine
Stephen W. Scherer: Hospital for Sick Children and University of Toronto
Sophie Molholm: Albert Einstein College of Medicine
Bryen A. Jordan: Albert Einstein College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Single-gene mutations in patients can help define genetic factors and molecular mechanisms underlying neurodevelopmental disorders. Here we describe individuals with monogenic heterozygous microdeletions in ANKS1B, a predicted risk gene for autism and neuropsychiatric diseases. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Neurons generated from patient-derived induced pluripotent stem cells demonstrate loss of the ANKS1B-encoded protein AIDA-1, a brain-specific protein highly enriched at neuronal synapses. A transgenic mouse model of Anks1b haploinsufficiency recapitulates a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction. Identification of the AIDA-1 interactome using quantitative proteomics reveals protein networks involved in synaptic function and the etiology of neurodevelopmental disorders. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome.

Date: 2019
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DOI: 10.1038/s41467-019-11437-w

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