title: Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation.
abstract: BACKGROUND
  Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).
  
  
  OBJECTIVE
  The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.
  
  
  METHODS
  The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.
  
  
  RESULTS
  LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.
  
  
  CONCLUSIONS
  Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
authors.affiliation: Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8537, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Irina
authors.initials: I
authors.lastname: Kazachkova
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ten
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D000886:Anthropometry; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006228:Hand Deformities, Congenital / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood; D034904:Lamin Type A / Q000235:genetics*; D020738:Leptin / Q000097:blood; D008060:Lipodystrophy / Q000150:complications / Q000235:genetics*; D008334:Mandible / Q000002:abnormalities; D008856:Microscopy, Fluorescence; D009154:Mutation; D011371:Progeria / Q000150:complications / Q000235:genetics*; D012885:Skinfold Thickness
chemical_list: D007328:Insulin; C494847:LMNA protein, human; D034904:Lamin Type A; D020738:Leptin
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