Compound heterozygosity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type A phenotype

J Clin Endocrinol Metab. 2007 Nov;92(11):4467-71. doi: 10.1210/jc.2007-0116. Epub 2007 Sep 11.


Context: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope.

Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients.

Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated.

Patient: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy.

Results: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient's cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1beta and histone H3 methylated at lysine 9.

Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Blotting, Western
  • Bone Diseases, Developmental / genetics*
  • Cells, Cultured
  • Craniofacial Abnormalities / genetics*
  • DNA Mutational Analysis
  • DNA, Complementary / genetics
  • Female
  • Fibroblasts / physiology
  • Fluorescent Antibody Technique
  • Heterozygote
  • Humans
  • Lamin Type A / genetics*
  • Lipodystrophy / genetics*
  • Microscopy, Electron
  • Mutagenesis
  • Mutation / genetics
  • Phenotype
  • Transfection


  • DNA, Complementary
  • LMNA protein, human
  • Lamin Type A