De Novo Variants in EMC1 Lead to Neurodevelopmental Delay and Cerebellar Degeneration and Affect Glial Function in Drosophila

Authors

Hyung-Lok Chung
Patrick Rump
Di Lu
Megan R Glassford
Jung-Wan Mok
Jawid Fatih
Adily Basal
Paul C Marcogliese
Oguz Kanca
Michele Rapp
Johanna M Fock
Erik-Jan Kamsteeg
James R Lupski
Austin Larson
Mark C Haninbal
Hugo Bellen
Tamar Harel

Publication Date

9-29-2022

Journal

Human Molecular Genetics

DOI

10.1093/hmg/ddac053

PMID

35234901

PMCID

PMC9523557

PubMedCentral® Posted Date

3-2-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Basic Helix-Loop-Helix Transcription Factors, Cerebellar Diseases, Drosophila, Drosophila Proteins, Intellectual Disability, Membrane Proteins, Nervous System Malformations, Neurodegenerative Diseases, Neurodevelopmental Disorders, Neuroglia, Repressor Proteins

Abstract

Background: The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration. Multiple families with biallelic variants have been published, yet to date, only a single report of a monoallelic variant has been described, and functional evidence is sparse.

Methods: Exome sequencing was used to investigate the genetic cause underlying severe developmental delay in three unrelated children. EMC1 variants were modeled in Drosophila, using loss-of-function (LoF) and overexpression studies. Glial-specific and neuronal-specific assays were used to determine whether the dysfunction was specific to one cell type.

Results: Exome sequencing identified de novo variants in EMC1 in three individuals affected by global developmental delay, hypotonia, seizures, visual impairment and cerebellar atrophy. All variants were located at Pro582 or Pro584. Drosophila studies indicated that imbalance of EMC1-either overexpression or knockdown-results in pupal lethality and suggest that the tested homologous variants are LoF alleles. In addition, glia-specific gene dosage, overexpression or knockdown, of EMC1 led to lethality, whereas neuron-specific alterations were tolerated.

Discussion: We establish de novo monoallelic EMC1 variants as causative of a neurological disease trait by providing functional evidence in a Drosophila model. The identified variants failed to rescue the lethality of a null allele. Variations in dosage of the wild-type EMC1, specifically in glia, lead to pupal lethality, which we hypothesize results from the altered stoichiometry of the multi-subunit protein complex EMC.