Compound heterozygosity for mutations in LMNA in a patient with myopathic and lipodystrophic Mandibuloacral Dysplasia type A phenotype.

Mandibuloacral dysplasia type A [MADA; OMIM#248370] is a rare progeroid syndrome characterised by dysmorphic craniofacial and skeletal features, lipodystrophy and metabolic complications. Most of Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope. Objective: Identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acro-osteolysis, 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 girl showing a MADA-like phenotype (MADA-het). Features include a hypoplastic mandible, acro-osteolysis, pointed nose, partial loss of subcutaneous 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. 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-1 ² (HP1²) and histone H3 methylated at lysine 9 (Me9H3). Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes which could be due to the combination of p.R527H and p.V440M alleles.