title: First missense mutation outside of SERAC1 lipase domain affecting intracellular cholesterol trafficking.
abstract: We report the clinical and genetic findings in a Spanish boy who presented MEGDEL syndrome, a very rare inborn error of metabolism. Whole-exome sequencing uncovered a new homozygous mutation in the serine active site containing 1 (SERAC1) gene, which is essential for both mitochondrial function and intracellular cholesterol trafficking. Functional studies in patient fibroblasts showed that p.D224G mutation affects the intracellular cholesterol trafficking. Only three missense mutations in this gene have been described before, being p.D224G the first missense mutation outside of the SERAC1 serine-lipase domain. Therefore, we conclude that the defect in cholesterol trafficking is not limited to alterations in this specific part of the protein.
authors.affiliation: Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Centro de Actividades Ambulatorias (CAA), 6ª Planta, Bloque E, Avda. Córdoba s/n, E-28041, Madrid, Spain.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Rodríguez-García
authors.affiliation: Unidad Pediátrica de Enfermedades Raras, Enfermedades Mitocondriales y Metabólicas Hereditarias, Hospital 12 de Octubre, E-28041, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Hernández
authors.affiliation: Unidad Pediátrica de Neuroradiología, Hospital 12 de Octubre, E-28041, Madrid, Spain.
authors.forename: Ana Martínez
authors.initials: AM
authors.lastname: de Aragón
authors.affiliation: Unidad Pediátrica de Enfermedades Raras, Enfermedades Mitocondriales y Metabólicas Hereditarias, Hospital 12 de Octubre, E-28041, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041, Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: García-Silva
authors.affiliation: Unidad Pediátrica de Enfermedades Raras, Enfermedades Mitocondriales y Metabólicas Hereditarias, Hospital 12 de Octubre, E-28041, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Quijada-Fraile
authors.affiliation: Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Centro de Actividades Ambulatorias (CAA), 6ª Planta, Bloque E, Avda. Córdoba s/n, E-28041, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041, Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arenas
authors.affiliation: Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Centro de Actividades Ambulatorias (CAA), 6ª Planta, Bloque E, Avda. Córdoba s/n, E-28041, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Martín
authors.affiliation: Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Centro de Actividades Ambulatorias (CAA), 6ª Planta, Bloque E, Avda. Córdoba s/n, E-28041, Madrid, Spain. fmartinez@h12o.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041, Madrid, Spain. fmartinez@h12o.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martínez-Azorín
mesh_terms: D001692:Biological Transport / Q000235:genetics; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000235:genetics*; D020134:Catalytic Domain / Q000235:genetics; D002648:Child; D002784:Cholesterol / Q000378:metabolism*; D003241:Consanguinity; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008049:Lipase / Q000737:chemistry; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D002784:Cholesterol; D002265:Carboxylic Ester Hydrolases; C576043:SERAC1 protein, human; D008049:Lipase
keywords: Cholesterol; MEGDEL syndrome; Mitochondria; SERAC1; WES; mtDNA