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Human Molecular Genetics Advance Access published online on July 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl172
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received March 21, 2006
Accepted June 5, 2006

Article

Compound heterozygosity for mutations in LMNA causes a Progeria Syndrome without prelamin A accumulation

Valerie L.R.M. Verstraeten 1 *, Jos L.V. Broers 2, Maurice A.M. van Steensel 3, Sophie Zinn-Justin 4, Frans C.S. Ramaekers 5, Peter M. Steijlen 3, Miriam Kamps 6, Helma J.H. Kuijpers 7, Diane Merckx 8, Hubert J.M. Smeets 8, Raoul C.M. Hennekam 9, Carlo L.M. Marcelis 10, and Arthur van den Wijngaard 8

1 Department of Dermatology, University Hospital Maastricht, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands; Research Institute for Growth and Development (GROW), University of Maastricht, the Netherlands
2 Department of Molecular Cell Biology, University of Maastricht, the Netherlands; Department of Biomechanics and Tissue Engineering, Faculty of Biomedical Engineering, Technical University of Eindhoven, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, the Netherlands
3 Department of Dermatology University Hospital Maastricht, the Netherlands; Research Institute for Growth and Development (GROW), University of Maastricht, the Netherlands
4 Département d'Ingénierie et d'Etudes des Protéines, CEA Saclay, Gif-sur-Yvette, France
5 Department of Molecular Cell Biology, University of Maastricht, the Netherlands; Research Institute for Growth and Development (GROW), University of Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, the Netherlands
6 Department of Dermatology University Hospital Maastricht, the Netherlands; Department of Molecular Cell Biology, University of Maastricht, the Netherlands; Research Institute for Growth and Development (GROW), University of Maastricht, the Netherlands
7 Department of Molecular Cell Biology, University of Maastricht, the Netherlands
8 Department of Clinical Genetics, University Hospital Maastricht, the Netherlands
9 Institute of Child Health, University College London, UK; Department of Pediatrics, Academic Medical Center, Univeristy of Amsterdam, the Netherlands
10 Department of Clinical Genetics, Radboud University Nijmegen Medical Centre, the Netherlands

* To whom correspondence should be addressed.
Valerie L.R.M. Verstraeten, E-mail: vve{at}sder.azm.nl


  Abstract

LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a two-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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