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

Lombardi F, Gullotta F, Columbaro M, Filareto A, D'Adamo M, Vielle A, Guglielmi V, Nardone AM, Azzolini V, Grosso E, Lattanzi G, D'Apice MR, Masala S, Maraldi NM, Sbraccia P, Novelli G
Source: J Clin Endocrinol Metab
Publication Date: (2007)
Issue: 92(11): 4467-71
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Species: human
Tissue Origin: kidney
Nucleofectorâ„¢ I/II/2b
Context: 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 beta (HP1beta) 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.