Conflict of interest: none.
LMNA-associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset
Article first published online: 10 MAY 2013
Copyright © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 7, pages 1599–1611, July 2013
How to Cite
2013. LMNA-associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset. Am J Med Genet Part A 161A:1599–1611., , , , , , , .
- Issue published online: 19 JUN 2013
- Article first published online: 10 MAY 2013
- Manuscript Accepted: 11 MAR 2013
- Manuscript Received: 28 NOV 2012
- W.W. Smith Charitable Trust
- Howard Hughes Medical Institute
- National Institutes of Health. Grant Number: RO1 GM41223
- prelamin A;
- lamin A/C;
- atypical Werner syndrome;
- atypical progeria;
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. © 2013 Wiley Periodicals, Inc.