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- Title
Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.
- Authors
Verstraeten, Valerie L.R.M.; Broers, Jos L.V.; van Steensel, Maurice A.M.; Zinn-Justin, Sophie; Ramaekers, Frans C.S.; Steijlen, Peter M.; Kamps, Miriam; Kuijpers, Helma J.H.; Merckx, Diane; Smeets, Hubert J.M.; Hennekam, Raoul C.M.; Marcelis, Carlo L.M.; van den Wijngaard, Arthur
- Abstract
LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson–Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect a conserved region within the C-terminal globular domain of A-type lamins, defining a progeria hot spot. The nuclei of the patient showed no prelamin A accumulation. In general, the nuclear phenotype did not correspond to that previously described for HGPS. Instead, honeycomb figures predominated and nuclear blebs with reduced/absent expression of B-type lamins could be detected. The healthy heterozygous parents showed similar nuclear changes, although in a smaller percentage of nuclei. Treatment with a farnesylation inhibitor resulted in accumulation of prelamin A at the nuclear periphery, in annular nuclear membrane plaques and in intra/trans-nuclear membrane invaginations. In conclusion, these findings suggest a critical role for the C-terminal globular lamin A/C region in nuclear structure and support a major contribution of abnormal assembly to the progeroid phenotype. In contrast to earlier suggestions, we show that prelamin A accumulation is not the major determinant of the progeroid phenotype.
- Publication
Human Molecular Genetics, 2006, Vol 15, Issue 16, p2509
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddl172