Biallelic BECN1 variants cause neurodevelopmental disorders via AMPA receptor dysregulation
- 1Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Abstract
Genetic regulation of neurodevelopmental disorders that impair brain development and social interaction is complex and poorly understood. Although emerging evidence suggests a link between neurodevelopmental disorders and autophagy deficits, congenital autophagy gene disorders are rare in humans, and underlying molecular mechanisms remain unknown. Here we demonstrate that the autophagy protein BECN1 is a regulator of neuronal and social development in vertebrate species. We identify rare deleterious biallelic BECN1 variants that cause neurodevelopmental disorders in two unrelated families. Becn1 disruption also causes neuronal and social developmental defects in mouse and zebrafish models. BECN1 serves as an adaptor to recruit Arc to the E3 ubiquitin ligase UBE3A for polyubiquitination and degradation, thereby maintaining postsynaptic AMPA receptor (AMPAR) stability, AMPAR-mediated excitatory neurotransmission, and normal social interaction. Thus, our study illustrates new biology and a non-canonical mechanism by which BECN1 regulates neurodevelopment in humans, mice and zebrafish, via a crosstalk with the ubiquitin-proteasomal machinery.
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BibTeX
@misc{kuramoto2026biallelic,
title = {{Biallelic BECN1 variants cause neurodevelopmental disorders via AMPA receptor dysregulation}},
author = {K. Kuramoto and F. Ullah and P. Liang and I. M. Ramirez and L. AlAbdi and B. Feng and M. Sakurai and M.-S. Kang and H. Dong and M. Oyeyemi and Z. Qin and M. A. Coghlan and A. Sharma and A. Mercier and A. McRae and A. Belmadani and A. Contractor and O. Abuyousef and M. O. Hashem and A. Alhashem and S. Maddirevula and F. Alkuraya and Y. He and E. E. Davis and C. He},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.26365182},
url = {https://www.medrxiv.org/content/10.64898/2026.10.13.26365182v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Biallelic BECN1 variants cause neurodevelopmental disorders via AMPA receptor dysregulation
AU - K. Kuramoto
AU - F. Ullah
AU - P. Liang
AU - I. M. Ramirez
AU - L. AlAbdi
AU - B. Feng
AU - M. Sakurai
AU - M.-S. Kang
AU - H. Dong
AU - M. Oyeyemi
AU - Z. Qin
AU - M. A. Coghlan
AU - A. Sharma
AU - A. Mercier
AU - A. McRae
AU - A. Belmadani
AU - A. Contractor
AU - O. Abuyousef
AU - M. O. Hashem
AU - A. Alhashem
AU - S. Maddirevula
AU - F. Alkuraya
AU - Y. He
AU - E. E. Davis
AU - C. He
PY - 2026
DA - 2026/10/13
PB - medRxiv
DO - 10.64898/2026.10.13.26365182
UR - https://www.medrxiv.org/content/10.64898/2026.10.13.26365182v1
AB - Genetic regulation of neurodevelopmental disorders that impair brain development and social interaction is complex and poorly understood. Although emerging evidence suggests a link between neurodevelopmental disorders and autophagy deficits, congenital autophagy gene disorders are rare in humans, and underlying molecular mechanisms remain unknown. Here we demonstrate that the autophagy protein BECN1 is a regulator of neuronal and social development in vertebrate species. We identify rare deleterious biallelic BECN1 variants that cause neurodevelopmental disorders in two unrelated families. Becn1 disruption also causes neuronal and social developmental defects in mouse and zebrafish models. BECN1 serves as an adaptor to recruit Arc to the E3 ubiquitin ligase UBE3A for polyubiquitination and degradation, thereby maintaining postsynaptic AMPA receptor (AMPAR) stability, AMPAR-mediated excitatory neurotransmission, and normal social interaction. Thus, our study illustrates new biology and a non-canonical mechanism by which BECN1 regulates neurodevelopment in humans, mice and zebrafish, via a crosstalk with the ubiquitin-proteasomal machinery.
ER -