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. Patients 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.
Compound heterozygosity for mutations in LMNA in a patient with myopathic and lipodystrophic Mandibuloacral Dysplasia type A phenotype.
Columbaro M;Lattanzi G;
2007
Abstract
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. Patients 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
