Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype
| Autor: | Anna Maria Nardone, Valeria Guglielmi, Nadir M. Maraldi, Valeria Azzolini, Enrico Grosso, Francesca Gullotta, Paolo Sbraccia, Giuseppe Novelli, Marta Columbaro, Anne Vielle, Maria Rosaria D'Apice, Monica D’Adamo, Giovanna Lattanzi, Francesca Lombardi, Antonio Filareto, Salvatore Masala |
|---|---|
| Přispěvatelé: | 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. |
| Rok vydání: | 2007 |
| Předmět: |
Fluorescent Antibody Technique
Alleles Cells Cultured Craniofacial Abnormalities Transfection Mutation Female Phenotype Heterozygote Blotting Western Fibroblasts Humans Microscopy Electron Bone Diseases Developmental Mutagenesis Adult DNA Mutational Analysis Lipodystrophy DNA Complementary Lamin Type A Settore MED/09 - Medicina Interna Endocrinology Diabetes and Metabolism Clinical Biochemistry Compound heterozygosity Biochemistry LMNA Endocrinology Complementary Missense mutation Developmental Settore MED/49 - Scienze Tecniche Dietetiche Applicate Microscopy Cultured Blotting Acroosteolysis Bone Diseases medicine.symptom Western medicine.medical_specialty Cells Context (language use) Biology Electron Settore MED/36 - Diagnostica per Immagini e Radioterapia Internal medicine medicine Biochemistry (medical) DNA medicine.disease Mandibuloacral dysplasia Settore MED/03 - Genetica Medica Dysplasia |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 92:4467-4471 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2007-0116 |
| Popis: | 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-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|