title: Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.
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.
authors.affiliation: Department of Dermatology, University Hospital Maastricht, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands. vve@sder.azm.nl
authors.forename: Valerie L R M
authors.initials: VL
authors.lastname: Verstraeten
authors.forename: Jos L V
authors.initials: JL
authors.lastname: Broers
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Sophie
authors.initials: S
authors.lastname: Zinn-Justin
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Peter M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: Miriam
authors.initials: M
authors.lastname: Kamps
authors.forename: Helma J H
authors.initials: HJ
authors.lastname: Kuijpers
authors.forename: Diane
authors.initials: D
authors.lastname: Merckx
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Carlo L M
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Arthur
authors.initials: A
authors.lastname: van den Wijngaard
mesh_terms: D000328:Adult; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006579:Heterozygote; D006801:Humans; D021621:Imaging, Three-Dimensional; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000032:analysis / Q000235:genetics*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D011371:Progeria / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics*; D011498:Protein Precursors / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects; D011859:Radiography
chemical_list: C096856:FTI 277; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D008148:Lovastatin; D008715:Methionine