# ANKS1B haploinsufficiency in a novel brain disorder

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $463,050

## Abstract

Neurodevelopmental disorders (NDDs) are highly prevalent brain diseases with enormous social and economic
impacts. Failure to understand their causative molecular and cellular mechanisms is largely responsible for the
paucity of available therapies. However, NDDs are highly heritable and the identification of causative single
gene mutations in patients will help define underlying genetic risk factors and molecular abnormalities. We
recently identified patients around the world harboring heterozygous and monogenic deletions of the ANKS1B
gene. Clinical analyses reveal that affected individuals present with a spectrum of neurodevelopmental
phenotypes, including autism, and speech and motor deficits. Our findings formalize a link between ANKS1B
haploinsufficiency and a previously undefined syndrome we term AnkSyd. Because the mechanisms linking
ANSK1B to essential cellular functions dysregulated in AnkSyd are unknown, elucidating ANKS1B function
represents a key opportunity to define molecular mechanisms contributing to NDDs and normal brain function.
The long-term goal of the proposed research is to define the mechanisms underlying AnkSyd and identify
therapeutic targets. ANKS1B encodes for AIDA-1, a brain specific protein that is one of the most abundant
proteins at neuronal synapses. Our lab found that AIDA-1 is specifically enriched at postsynaptic densities
where it controls NMDA receptor (NMDAR) function by regulating the synaptic localization and function of
GluN2B subunits of NMDARs. The proposed research will test the hypothesis that NMDAR dysfunction
contributes to AnkSyd. Toward this purpose, we generated induced pluripotent stem cells (iPSCs) and neurons
from patients and unaffected family members, as well as a transgenic mouse model that displays behavioral
correlates of patient phenotypes. 
Overall, this proposal seeks to understand the pathophysiology of AnkSyd, a newly identified genetic syndrome
presenting with autism and neurodevelopmental delays. As a monogenic disease with confirmed ANKS1B
haploinsufficiency, studying AnkSyd will allow us to clearly link AIDA-1 dysfunction to cellular and behavioral
outcomes. The successful completion of these experiments will reveal that NMDAR dysfunction contributes to
AnkSyd pathophysiology and that ANKS1B haploinsufficiency disrupts a specific mechanism linking AIDA-1 to
GluN2B. Finally, these experiments will determine the therapeutic potential of rescuing GluN2B function or
other abnormal molecular pathways identified in AnkSyd models.

## Key facts

- **NIH application ID:** 10071609
- **Project number:** 1R01NS118820-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Bryen Alexander Jordan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,050
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071609

## Citation

> US National Institutes of Health, RePORTER application 10071609, ANKS1B haploinsufficiency in a novel brain disorder (1R01NS118820-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071609. Licensed CC0.

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