De novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila.

TitleDe novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila.
Publication TypeJournal Article
Year of Publication2022
AuthorsChung, H-L, Rump, P, Lu, D, Glassford, MR, Mok, J-W, Fatih, J, Basal, A, Marcogliese, PC, Kanca, O, Rapp, M, Fock, JM, Kamsteeg, E-J, Lupski, JR, Larson, A, Haninbal, MC, Bellen, H, Harel, T
JournalHum Mol Genet
Date Published2022 Sep 29
KeywordsAnimals, 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

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.

Alternate JournalHum Mol Genet
PubMed ID35234901
PubMed Central IDPMC9523557
Grant ListR24 OD031447 / OD / NIH HHS / United States
MFE-164712 / / CIHR / Canada
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U01 HG007703 / NH / NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States

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