{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T22:22:01Z","timestamp":1792707721679,"version":"4.5.0"},"reference-count":13,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T00:00:00Z","timestamp":1728864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>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 (<jats:italic>ME2<\/jats:italic>) 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 <jats:italic>ME2<\/jats:italic> 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 <jats:italic>ME2<\/jats:italic>\u2010associated recessive NDD.<\/jats:p>","DOI":"10.1111\/cge.14632","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T02:18:53Z","timestamp":1728958733000},"page":"201-207","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>ME2<\/scp> Deficiency Is Associated With Recessive Neurodevelopmental Disorder"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-395X","authenticated-orcid":false,"given":"Naif A. M.","family":"Almontashiri","sequence":"first","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essa","family":"Alharby","sequence":"additional","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Saleh","sequence":"additional","affiliation":[{"name":"Section of Medical Genetics Children's Specialist Hospital  King Fahad Medical City Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Abu\u2010Farha","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department Dasman Diabetes Institute  Kuwait City Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Alasmari","sequence":"additional","affiliation":[{"name":"Section of Medical Genetics Children's Specialist Hospital  King Fahad Medical City Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinella","family":"Gebbia","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute Mount Sinai Hospital  Toronto Ontario Canada"},{"name":"Donnelly Centre and Department of Molecular Genetics University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Hiesl","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience Goethe University  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy W. A.","family":"Peake","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami Samir","family":"Amr","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital Harvard Medical School  Cambridge Massachusetts USA"},{"name":"Laboratory for Molecular Medicine, Personalized Medicine Mass General Brigham  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eckhard","family":"Boles","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience Goethe University  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick P.","family":"Roth","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute Mount Sinai Hospital  Toronto Ontario Canada"},{"name":"Department of Computational and Systems Biology University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jehad","family":"Abubaker","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department Dasman Diabetes Institute  Kuwait City Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)49948-6"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602954200"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11776"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04930-y"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10044"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-61495-0"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2188-x"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.6037607"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.180.11.2875-2882.1998"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1086\/426735"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.00270.x"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2006.06.001"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14632","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T03:41:52Z","timestamp":1736739712000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,14]]},"references-count":13,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1111\/cge.14632"],"URL":"https:\/\/doi.org\/10.1111\/cge.14632","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,14]]},"assertion":[{"value":"2024-09-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}