title: Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome.
abstract: Accelerated aging syndromes represent a valuable source of information about the molecular mechanisms involved in normal aging. Here, we describe a progeroid syndrome that partially phenocopies Hutchinson-Gilford progeria syndrome (HGPS) but also exhibits distinctive features, including the absence of cardiovascular deficiencies characteristic of HGPS, the lack of mutations in LMNA and ZMPSTE24, and a relatively long lifespan of affected individuals. Exome sequencing and molecular analysis in two unrelated families allowed us to identify a homozygous mutation in BANF1 (c.34G>A [p.Ala12Thr]), encoding barrier-to-autointegration factor 1 (BAF), as the molecular abnormality responsible for this Mendelian disorder. Functional analysis showed that fibroblasts from both patients have a dramatic reduction in BAF protein levels, indicating that the p.Ala12Thr mutation impairs protein stability. Furthermore, progeroid fibroblasts display profound abnormalities in the nuclear lamina, including blebs and abnormal distribution of emerin, an interaction partner of BAF. These nuclear abnormalities are rescued by ectopic expression of wild-type BANF1, providing evidence for the causal role of this mutation. These data demonstrate the utility of exome sequencing for identifying the cause of rare Mendelian disorders and underscore the importance of nuclear envelope alterations in human aging.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.forename: Victor
authors.initials: V
authors.lastname: Quesada
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.forename: Rubén
authors.initials: R
authors.lastname: Cabanillas
authors.forename: Juan
authors.initials: J
authors.lastname: Cadiñanos
authors.forename: Julia M
authors.initials: JM
authors.lastname: Fraile
authors.forename: Gonzalo R
authors.initials: GR
authors.lastname: Ordóñez
authors.forename: Diana A
authors.initials: DA
authors.lastname: Puente
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.forename: Miriam
authors.initials: M
authors.lastname: Fanjul-Fernández
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000328:Adult; D002467:Cell Nucleus; D002478:Cells, Cultured; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: C501959:BANF1 protein, human; D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; C092710:emerin