title: A leaky splicing mutation in NFU1 is associated with a particular biochemical phenotype. Consequences for the diagnosis.
abstract: Mutations in NFU1 were recently identified in patients with fatal encephalopathy. NFU1 is an iron-sulfur cluster protein necessary for the activity of the mitochondrial respiratory chain complexes I-II and the synthesis of lipoic acid. We report two NFU1 compound heterozygous individuals with normal complex I and lipoic acid-dependent enzymatic activities and low, but detectable, levels of lipoylated proteins. We demonstrated a leaky splicing regulation due to a splice site mutation (c.545+5G>A) that produces small amounts of wild type NFU1 mRNA that might result in enough protein to partially lipoylate and restore the activity of lipoic acid-dependent enzymes and the assembly and activity of complex I. These results allowed us to gain insights into the molecular basis underlying this disease and should be considered for the diagnosis of NFU1 patients.
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Xènia
authors.initials: X
authors.lastname: Ferrer-Cortès
authors.affiliation: Clinica Universitária de Navarra, Facultad Medicina, Pamplona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Narbona
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Bujan
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Leslie
authors.initials: L
authors.lastname: Matalonga
authors.affiliation: Hospital Vall d'Hebron, UAB, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Del Toro
authors.affiliation: Hospital Vall d'Hebron, UAB, Barcelona, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Arranz
authors.affiliation: Hospital Vall d'Hebron, UAB, Barcelona, Spain.
authors.forename: Encarnació
authors.initials: E
authors.lastname: Riudor
authors.affiliation: Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain.
authors.forename: Angels
authors.initials: A
authors.lastname: Garcia-Cazorla
authors.affiliation: Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.affiliation: Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: O'Callaghan
authors.affiliation: Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain.
authors.forename: Mercé
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Montero
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Arias
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: García-Villoria
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain; CSIC, Barcelona, Spain.
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain. Electronic address: aribes@clinic.ub.es.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.affiliation: Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain. Electronic address: ftort@ciberer.es.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
mesh_terms: D001928:Brain Diseases, Metabolic / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D054878:Lipoylation / Q000235:genetics; D008297:Male; D009154:Mutation; D022821:RNA Splice Sites; D012326:RNA Splicing; D011859:Radiography
chemical_list: D002352:Carrier Proteins; C426067:NFU1 protein, human; D022821:RNA Splice Sites
keywords: Iron–sulfur cluster; Lipoic acid; Metabolic disorder; Mitochondrial cofactor; Mitochondrial disease; NFU1