Human Molecular Genetics Advance Access originally published online on July 6, 2006
Human Molecular Genetics 2006 15(16):2509-2522; doi:10.1093/hmg/ddl172
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Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation
1 Department of Dermatology and 2 Department of Clinical Genetics, University Hospital Maastricht, The Netherlands, 3 Department of Molecular Cell Biology, 4 Research Institute for Growth and Development (GROW) and 5 Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands, 6 Department of Biomechanics and Tissue Engineering, Faculty of Biomedical Engineering, Technical University of Eindhoven, The Netherlands, 7 Département d'Ingénierie et d'Etudes des Protéines, CEA Saclay, France, 8 Institute of Child Health, University College London, UK, 9 Department of Pediatrics, Academic Medical Center, University of Amsterdam, T, The Netherlands and 10 Department of Clinical Genetics, Radboud University Nijmegen Medical Centre, The, Netherlands
* To whom correspondence should be addressed at: Department of Dermatology, University Hospital Maastricht, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel: +31 433875641; Fax: +31 433877293; Email: vve{at}sder.azm.nl
Received March 21, 2006; Accepted June 5, 2006
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.
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