ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder.
ME2
Krebs cycle
NDD
loss of function
malate
recessive
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
14 Oct 2024
14 Oct 2024
Historique:
revised:
27
09
2024
received:
06
09
2024
accepted:
30
09
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
14
10
2024
Statut:
aheadofprint
Résumé
Malate is an important dicarboxylic acid produced from fumarate in the tricarboxylic acid cycle. Deficiencies of fumarate hydrolase (FH) and malate dehydrogenase (MDH), responsible for malate formation and metabolism, respectively, are known to cause recessive forms of neurodevelopmental disorders (NDDs). The malic enzyme isoforms, malic enzyme 1 (ME1) and 2 (ME2), are required for the conversion of malate to pyruvate. To date, there have been no reports linking deficiency of either malic enzyme isoforms to any Mendelian disease in humans. We report a patient presenting with NDD, subtle dysmorphic features, resolved dilated cardiomyopathy, and mild blood lactate elevation. Whole exome sequencing (WES) revealed a homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in the malic enzyme 2 (ME2) gene resulting in truncated and unstable ME2 protein in vitro. Subsequent deletion of the yeast ortholog of human ME2 (hME2) resulted in growth arrest, which was rescued by overexpression of hME2, strongly supporting an important role of ME2 in mitochondrial function. Our results also support the pathogenicity and candidacy of the ME2 gene and variant in association with NDD. To our knowledge, this is the first report of a Mendelian human disease resulting from a biallelic variant in the ME encoding gene. Future studies are warranted to confirm ME2-associated recessive NDD.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Research, Development and Innovation Authority, Kingdom of Saudi Arabia
ID : 12996-iau-2023-TAU-R-3-1-HW-
Organisme : Canadian Institutes of Health Research Foundation Grant
ID : FDN-159926
Informations de copyright
© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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