{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:25:40Z","timestamp":1790393140008,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T00:00:00Z","timestamp":1643155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>BCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation.<\/jats:p>","DOI":"10.3390\/genes13020233","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T11:02:53Z","timestamp":1643194973000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8921-2012","authenticated-orcid":false,"given":"Alice","family":"Maguolo","sequence":"first","affiliation":[{"name":"Department of Mother and Child, University of Verona, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Rodella","sequence":"additional","affiliation":[{"name":"Department of Mother and Child, University of Verona, I-37126 Verona, Italy"},{"name":"Inherited Metabolic Diseases Unit and Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Giorgetti","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Verona, Strada Le Grazie 15, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Nicolodi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Verona, Strada Le Grazie 15, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Forschungszentrum J\u00fclich, D-52425 J\u00fclich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Dianin","sequence":"additional","affiliation":[{"name":"Inherited Metabolic Diseases Unit and Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, I-37126 Verona, Italy"},{"name":"Pediatric Clinic AOUI of Verona, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1343-8434","authenticated-orcid":false,"given":"Gaetano","family":"Cantalupo","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Integrata, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Monge","sequence":"additional","affiliation":[{"name":"Inherited Metabolic Diseases Unit and Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Carcereri","sequence":"additional","affiliation":[{"name":"Inherited Metabolic Diseases Unit and Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, I-37126 Verona, Italy"},{"name":"Pediatric Clinic AOUI of Verona, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita Lucia","family":"De Bernardi","sequence":"additional","affiliation":[{"name":"Pediatric Clinic AOUI of Verona, I-37126 Verona, Italy"},{"name":"Department of Molecular Medicine and Biotecnology, AOU Federico II, I-80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7100-4581","authenticated-orcid":false,"given":"Massimo","family":"Delledonne","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Verona, Strada Le Grazie 15, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Pasini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascia","family":"Campostrini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florina","family":"Ion Popa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Piacentini","sequence":"additional","affiliation":[{"name":"Department of Mother and Child, University of Verona, I-37126 Verona, Italy"},{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Teofoli","sequence":"additional","affiliation":[{"name":"Department of Mother and Child, University of Verona, I-37126 Verona, Italy"},{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Vincenzi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Camilot","sequence":"additional","affiliation":[{"name":"Department of Mother and Child, University of Verona, I-37126 Verona, Italy"},{"name":"Department of Pediatrics, The Regional Center for Neonatal Screening, Diagnosis and Treatment of Inherited Congenital Metabolic and Endocrinological Diseases, AOUI, I-37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-8187","authenticated-orcid":false,"given":"Andrea","family":"Bordugo","sequence":"additional","affiliation":[{"name":"Inherited Metabolic Diseases Unit and Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, I-37126 Verona, Italy"},{"name":"Pediatric Clinic AOUI of Verona, I-37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.nu.04.070184.002205","article-title":"Branched-Chain Amino Acid Metabolism","volume":"4","author":"Harper","year":"1984","journal-title":"Annu. 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