{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:38:10Z","timestamp":1760236690362,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Research Institute of Santiago (IDIS)","award":["PhD grant from Pre-Doctoral scholarship"],"award-info":[{"award-number":["PhD grant from Pre-Doctoral scholarship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G&gt;A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient\u2019s DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient\u2019s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient\u2019s fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant.<\/jats:p>","DOI":"10.3390\/ijms222413484","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T21:47:36Z","timestamp":1639604856000},"page":"13484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1431-4644","authenticated-orcid":false,"given":"Sofia","family":"Barbosa-Gouveia","sequence":"first","affiliation":[{"name":"Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15706 Santiago de Compostela, Spain"},{"name":"Rare Diseases Networking Biomedical Research Centre (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3167-5919","authenticated-orcid":false,"given":"Maria E.","family":"V\u00e1zquez-Mosquera","sequence":"additional","affiliation":[{"name":"Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15706 Santiago de Compostela, Spain"},{"name":"Rare Diseases Networking Biomedical Research Centre (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emiliano","family":"Gonzalez-Vioque","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Service, Puerta de Hierro-Majadahonda University Hospital, 28222 Majadahonda, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3757-262X","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Hermida-Ameijeiras","sequence":"additional","affiliation":[{"name":"Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15706 Santiago de Compostela, Spain"},{"name":"Rare Diseases Networking Biomedical Research Centre (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-6008","authenticated-orcid":false,"given":"Laura L.","family":"Valverde","sequence":"additional","affiliation":[{"name":"Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15706 Santiago de Compostela, Spain"},{"name":"Rare Diseases Networking Biomedical Research Centre (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-9307","authenticated-orcid":false,"given":"Judith","family":"Armstrong-Moron","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Molecular and Genetic Medicine Section, Hospital Sant Joan de D\u00e9u and Institut de Recerca Sant Joan de D\u00e9u, 08950 Esplugues de Llobregat, Spain"},{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria del Carmen","family":"Fons-Estupi\u00f1a","sequence":"additional","affiliation":[{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Pediatric Neurology Department, Institut de Recerca Sant Joan de D\u00e9u, Sant Joan de D\u00e9u University Hospital, 08950 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7988-1984","authenticated-orcid":false,"given":"Liesbeth T.","family":"Wintjes","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3115-8882","authenticated-orcid":false,"given":"Antonia","family":"Kappen","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5227-3527","authenticated-orcid":false,"given":"Richard J.","family":"Rodenburg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4861-9905","authenticated-orcid":false,"given":"Maria L.","family":"Couce","sequence":"additional","affiliation":[{"name":"Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15706 Santiago de Compostela, Spain"},{"name":"Rare Diseases Networking Biomedical Research Centre (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"190126","DOI":"10.1098\/rsob.190126","article-title":"Mitochondria\u2014Hubs for regulating cellular biochemistry: Emerging concepts and networks","volume":"9","author":"Anderson","year":"2019","journal-title":"Open 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