title: Impact on bone of an estrogen receptor-alpha gene loss of function mutation.
abstract: BACKGROUND
  The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-alpha.
  
  
  OBJECTIVE
  Our objective was to assess the impact of a loss of function mutation in the ER-alpha gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-alpha heterozygosity on spine density and adult height in an extended pedigree.
  
  
  METHODS
  A longitudinal follow-up of the propositus with homozygous loss of function mutation of ER-alpha and single contact evaluation of the kindred were performed.
  
  
  METHODS
  Iliac crest bone biopsy and peripheral quantitative computed tomography of propositus with serial measures of areal spine bone mineral density (aBMD) by dual-energy x-ray absorptiometry and bone age were performed. Members of pedigree were evaluated for ER-alpha mutation carrier status and spine aBMD.
  
  
  RESULTS
  Bone biopsy revealed marked osteopenia (cortex: 641 microm), low trabecular volume (10.6%), decreased thickness (76.2 microm), normal trabecular number, and low activation frequency (0.099/yr). Radial periosteal circumference was similar, endosteal circumference larger, and trabecular and cortical volumetric bone mineral density markedly lower (158 and 1092 mg/cm(3), respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm(2)) decreased to 0.684 g/cm(2) (Z score -3.85) in 3.5 yr. Bone age advanced from 15-17.5 yr. Kindred analysis revealed that gene carriers had spine aBMD Z scores less than zero (P = 0.003), but carriers and nonmutant members were similar (-0.84 +/- 0.26 vs. -0.64 +/- 0.16).
  
  
  CONCLUSIONS
  Homozygous ER-alpha disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-alpha heterozygosity appears to not impair spine aBMD.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, Ohio 45267-0547, USA. smithep@email.uc.edu
authors.forename: Eric P
authors.initials: EP
authors.lastname: Smith
authors.forename: Bonny
authors.initials: B
authors.lastname: Specker
authors.forename: Bert E
authors.initials: BE
authors.lastname: Bachrach
authors.forename: K S
authors.initials: KS
authors.lastname: Kimbro
authors.forename: X J
authors.initials: XJ
authors.lastname: Li
authors.forename: Marian F
authors.initials: MF
authors.lastname: Young
authors.forename: Neal S
authors.initials: NS
authors.lastname: Fedarko
authors.forename: M J
authors.initials: MJ
authors.lastname: Abuzzahab
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Frank
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cohen
authors.forename: Dennis B
authors.initials: DB
authors.lastname: Lubahn
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
mesh_terms: D000328:Adult; D001827:Body Height; D015519:Bone Density; D016723:Bone Remodeling; D001842:Bone and Bones / Q000473:pathology*; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000032:analysis
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger