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

Francesca Lombardi, Francesca Gullotta, Marta Columbaro, Antonio Filareto, Monica D'Adamo, Anne Vielle, Valeria Guglielmi, Anna Maria Nardone, Valeria Azzolini, Enrico Grosso, Giovanna Lattanzi, Maria Rosaria D'Apice, Salvatore Masala, Nadir Mario Maraldi, Paolo Sbraccia, Giuseppe Novelli

Research output: Contribution to journalArticlepeer-review


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: TheLMNA 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-1β 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.

Original languageEnglish
Pages (from-to)4467-4471
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
Publication statusPublished - Nov 2007

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism


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