Biallelic BECN1 variants cause neurodevelopmental disorders via AMPA receptor dysregulation

BECN1

Biallelic deleterious BECN1 variants; loss of the adaptor function recruiting Arc to the UBE3A ubiquitin ligase, destabilizing postsynaptic AMPA receptors

The authors identify rare deleterious biallelic variants in BECN1, an autophagy protein, in patients with neurodevelopmental disorders from two unrelated families. Disruption of Becn1 also causes neuronal and social developmental defects in mouse and zebrafish. Mechanistically, BECN1 acts as an adaptor recruiting Arc to the E3 ubiquitin ligase UBE3A for polyubiquitination and degradation, thereby maintaining postsynaptic AMPA receptor stability, AMPA receptor-mediated excitatory neurotransmission and normal social interaction. The authors thus describe a non-canonical pathway through which BECN1 regulates neurodevelopment, in crosstalk with the ubiquitin-proteasome machinery.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The case combines two families, two animal models and a coherent molecular mechanism, and no human disease linked to BECN1 had been reported so far: this is a strong candidate recessive neurodevelopmental disorder gene. It is, however, a medRxiv preprint not peer-reviewed, and two families remain few to establish a solid gene-disease relationship. In practice, a biallelic BECN1 variant seen on an exome in a patient with a compatible phenotype is worth flagging and sharing, not yet reporting as causal.

Analysis by Dr Thibaut Benquey