title: Atypical progeroid syndrome due to heterozygous missense LMNA mutations.
abstract: BACKGROUND
  Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS).
  
  
  OBJECTIVE
  The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS.
  
  
  RESULTS
  We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients.
  
  
  CONCLUSIONS
  APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated 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. abhimanyu.garg@utsouthwestern.edu
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
authors.forename: Lalitha
authors.initials: L
authors.lastname: Subramanyam
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Vinaya
authors.initials: V
authors.lastname: Simha
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levine
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Yanick
authors.initials: Y
authors.lastname: Crow
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D000886:Anthropometry; D001823:Body Composition / Q000502:physiology; D001827:Body Height / Q000502:physiology; D002648:Child; D003057:Cockayne Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005951:Glucose Tolerance Test; D006225:Hand / Q000000981:diagnostic imaging; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D010641:Phenotype; D011371:Progeria / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D012867:Skin / Q000166:cytology / Q000378:metabolism; D055815:Young Adult
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A