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Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype

Departments of Biopathology and Diagnostic Imaging (F.L., F.G., A.F., A.V., A.M.N., M.R.D., G.N.), Internal Medicine (M.D., V.G., P.S.), and Diagnostic Imaging and Interventional Radiology (S.M.), University of Rome Tor Vergata, 00133 Rome, Italy; Institute of Molecular Genetics-Consiglio Nazionale dell Ricerche (M.C., G.L., N.M.M.), Unit of Bologna, c/o Istituti Ortopedici Rizzoli, 40136 Bologna, Italy; Laboratory of Rheumatology (V.A.) and Laboratory of Medical Genetics (E.G.), Azienda Ospedaliera San Giovanni Battista Torino, 10123 Torino, Italy; Fondazione Livio Patrizi (G.N.), 00100 Rome, Italy; and Department of Cardiovascular Medicine (G.N.), University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Professor Giuseppe Novelli, Department of Biopathology and Diagnostic Imaging, University of Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail: novelli{at}med.uniroma2.it.

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-1ß 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.

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