Journal Article

Compound heterozygosity for mutations in <i>LMNA</i> causes a progeria syndrome without prelamin A accumulation

Valerie L.R.M. Verstraeten, Jos L.V. Broers, Maurice A.M. van Steensel, Sophie Zinn-Justin, Frans C.S. Ramaekers, Peter M. Steijlen, Miriam Kamps, Helma J.H. Kuijpers, Diane Merckx, Hubert J.M. Smeets, Raoul C.M. Hennekam, Carlo L.M. Marcelis and Arthur van den Wijngaard

in Human Molecular Genetics

Volume 15, issue 16, pages 2509-2522
Published in print August 2006 | ISSN: 0964-6906
Published online July 2006 | e-ISSN: 1460-2083 | DOI:
Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation

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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.

Journal Article.  8367 words.  Illustrated.

Subjects: Genetics and Genomics

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