title: Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.
abstract: Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.
authors: Medicine, University of Washington, Seattle, Washington 98195-7470, USA.
authors: Fuki M
authors: FM
authors: Hisama
authors: Davor
authors: D
authors: Lessel
authors: Dru
authors: D
authors: Leistritz
authors: Katrin
authors: K
authors: Friedrich
authors: Kim L
authors: KL
authors: McBride
authors: Matthew T
authors: MT
authors: Pastore
authors: Gary S
authors: GS
authors: Gottesman
authors: Bidisha
authors: B
authors: Saha
authors: George M
authors: GM
authors: Martin
authors: Christian
authors: C
authors: Kubisch
authors: Junko
authors: J
authors: Oshima
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D002648:Child; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics*; D005091:Exons; D019066:Facies; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011371:Progeria / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D014898:Werner Syndrome / Q000235:genetics; D055815:Young Adult
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A