title: LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset.
abstract: Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Kane
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lindsay
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Jemima
authors.initials: J
authors.lastname: Barrowman
authors.forename: Colette
authors.initials: C
authors.lastname: Ap Rhys
authors.forename: Lisa
authors.initials: L
authors.lastname: Simonson
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Susan
authors.initials: S
authors.lastname: Michaelis
mesh_terms: D000328:Adult; D017668:Age of Onset; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics; D009685:Nuclear Envelope / Q000235:genetics / Q000648:ultrastructure; D011371:Progeria / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D046188:Protein Modification, Translational; D013577:Syndrome
chemical_list: D004791:Enzyme Inhibitors; C494847:LMNA protein, human; D034904:Lamin Type A; D051231:Farnesyltranstransferase