title: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
authors.affiliation: Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Gordon
authors.forename: Michael W
authors.initials: MW
authors.lastname: Glynn
authors.forename: Joel
authors.initials: J
authors.lastname: Singer
authors.forename: Laura
authors.initials: L
authors.lastname: Scott
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Robbins
authors.forename: Tracy Y
authors.initials: TY
authors.lastname: Moses
authors.forename: Peter
authors.initials: P
authors.lastname: Berglund
authors.forename: Amalia
authors.initials: A
authors.lastname: Dutra
authors.forename: Evgenia
authors.initials: E
authors.lastname: Pak
authors.forename: Sandra
authors.initials: S
authors.lastname: Durkin
authors.forename: Antonei B
authors.initials: AB
authors.lastname: Csoka
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Glover
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D002648:Child; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D034904:Lamin Type A / Q000032:analysis / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011371:Progeria / Q000235:genetics* / Q000473:pathology; D022821:RNA Splice Sites / Q000235:genetics; D013577:Syndrome; D024182:Uniparental Disomy / Q000235:genetics
chemical_list: D034904:Lamin Type A; D022821:RNA Splice Sites