title: A novel ADIPOQ mutation (p.M40K) impairs assembly of high-molecular-weight adiponectin and is associated with early-onset obesity and metabolic syndrome.
abstract: BACKGROUND
  The phenotypic effects of ADIPOQ mutations early in life, prior to type 2 diabetes onset, have not been studied.
  
  
  OBJECTIVE
  The objective of the study was to characterize the impact of a novel ADIPOQ mutation in vitro and in vivo.
  
  
  METHODS
  The design of the study was ADIPOQ screening, adiponectin oligomerization, and cardiometabolic phenotype assessment.
  
  
  METHODS
  Fourteen hypoadiponectinemic (<3 μg/mL) and 686 normoadiponectinemic young adults (23-25 y) were prospectively followed up since birth.
  
  
  METHODS
  Human and recombinant murine mutant adiponectin oligomerization, the proband's ADIPOQ and ADIPOR1/R2 adipose tissue (AT) expression, and cardiometabolic profile were measured.
  
  
  RESULTS
  The heterozygous ADIPOQ p.M40K mutation was identified in one hypoadiponectinemic male (2.4 μg/mL) and three other family members. Carriers presented a marked reduction of serum high-molecular weight to total adiponectin ratio when compared with controls (9.4% ± 1% vs 56.6% ± 13%; P < .05) and family noncarriers (9.4% ± 1% vs 42% ± 0.5%; P = .05). Both mRNA and protein levels of adiponectin were increased in the AT of the proband (2.3- and 1.6-fold, respectively). However, the high-molecular weight to total adiponectin ratio of adiponectin was decreased (3.3-fold). Moreover, the expressions of ADIPOR1 and ADIPOR2 were significantly down-regulated in the AT of the proband (6- and 1.2-fold, respectively). The results were confirmed by in vitro studies on the recombinant murine homologous mutation (p.M43K). The proband's cardiometabolic phenotype progression was further characterized: born small for gestational age and adolescence-onset obesity; insulin resistance (homeostasis assessment model of insulin resistance of 4.7), and dyslipidemia at 25 years; decreased high-molecular weight adiponectin (0.24 μg/mL = 10%), hypertension (180/120 mm Hg), steatosis (fat liver = 40% ± 6%), increased carotid intima-media thickness at 31 years, and type 2 diabetes (glycosylated hemoglobin = 6.6%) at 34 years of age. Of note, all of the affected family members presented features of metabolic syndrome.
  
  
  CONCLUSIONS
  The newly identified ADIPOQ p.M40K mutation associates with severe cardiometabolic dysfunction due to the impairment of high-molecular weight adiponectin complex formation.
authors.affiliation: Departments of Pediatrics (A.C.B., M.A.B., H.B., S.R.A.) and Internal Medicine (C.S.M., J.E.J., W.M., M.C.F.-F., M.d.C.), School of Medicine of Ribeirao Preto, University of Sao Paulo, 14049-900, Brazil; and Touchstone Diabetes Center (K.S., C.T., P.E.S.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Bueno
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Clarissa Silva
authors.initials: CS
authors.lastname: Martins
authors.forename: Jorge
authors.initials: J
authors.lastname: Elias Junior
authors.forename: Wallace
authors.initials: W
authors.lastname: Miranda
authors.forename: Caroline
authors.initials: C
authors.lastname: Tao
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Foss-Freitas
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Barbieri
authors.forename: Heloísa
authors.initials: H
authors.lastname: Bettiol
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Sonir R
authors.initials: SR
authors.lastname: Antonini
mesh_terms: D052242:Adiponectin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D008970:Molecular Weight; D020125:Mutation, Missense; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization / Q000235:genetics*; D055815:Young Adult
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D008715:Methionine; D008239:Lysine