Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation

V.L.R.M. Verstraeten, J.L.V. Broers, M.A.M Steensel, van, S. Zinn-Justin, F.C.S. Ramaekers, P.M. Steijlen, M.A. Kamps, H.J.H. Kuijpers, D. Merckx, H.J.M. Smeets, R.C.M. Hennekam, C.L.M. Marcelis, A. Wijngaard, van den

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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.
Original languageEnglish
Pages (from-to)2509-22
JournalHuman Molecular Genetics
Issue number16
Publication statusPublished - 2006


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