title: A novel mechanism of inherited TBG deficiency: mutation in a liver-specific enhancer.
abstract: BACKGROUND
  T4-binding globulin (TBG), a protein secreted by the liver, is the main thyroid hormone (TH) transporter in human serum. TBG deficiency is characterized by reduced serum TH levels, but normal free TH and TSH and absent clinical manifestations. The inherited form of TBG deficiency is usually due to a mutation in the TBG gene located on the X-chromosome.
  
  
  OBJECTIVE
  Among the 75 families with X-chromosome-linked TBG deficiency identified in our laboratory, no mutations in the TBG gene were found in four families. The aim of the study was to identify the mechanism of TBG deficiency in these four families using biochemical and genetic studies.
  
  
  METHODS
  Observational cohort, prospective.
  
  
  METHODS
  University research center.
  
  
  METHODS
  Four families with inherited TBG deficiency and no mutations in the TBG gene.
  
  
  METHODS
  Clinical evaluation, thyroid function tests, and targeted resequencing of 1 Mb of the X-chromosome.
  
  
  RESULTS
  Next-generation sequencing identified a novel G to A variant 20 kb downstream of the TBG gene in all four families. In silico analysis predicted that the variant resides within a liver-specific enhancer. In vitro studies confirmed the enhancer activity of a 2.2-kb fragment of genomic DNA containing the novel variant and showed that the mutation reduces the activity of this enhancer. The affected subjects share a haplotype of 8 Mb surrounding the mutation, and the most recent common ancestor among the four families was estimated to be 19.5 generations ago (95% confidence intervals, 10.4-37).
  
  
  CONCLUSIONS
  To our knowledge, the present study is the first report of an inherited endocrine disorder caused by a mutation in an enhancer region.
authors.affiliation: Departments of Medicine (A.M.F., T.P., J.F., A.P., V.T., R.E.W., A.M.D., S.R.), Pediatrics (R.E.W., S.R.), and Human Genetics (C.D.B., A.P., K.P.W., M.N.), and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; Department of Endocrinology and Metabolic Diseases (L.C.M.), University of Duisburg-Essen, Essen 45147, Germany; and Department of Medicine (K.W.), Weill Cornell Medical College, The Methodist Hospital, Houston, Texas 77030.
authors.forename: Alfonso Massimiliano
authors.initials: AM
authors.lastname: Ferrara
authors.forename: Theodora
authors.initials: T
authors.lastname: Pappa
authors.forename: Jiao
authors.initials: J
authors.lastname: Fu
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.forename: April
authors.initials: A
authors.lastname: Peterson
authors.forename: Lars C
authors.initials: LC
authors.lastname: Moeller
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wyne
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
authors.forename: Anna
authors.initials: A
authors.lastname: Pluzhnikov
authors.forename: Vassily
authors.initials: V
authors.lastname: Trubetskoy
authors.forename: Marcelo
authors.initials: M
authors.lastname: Nobrega
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Dumitrescu
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004742:Enhancer Elements, Genetic; D005260:Female; D006239:Haplotypes; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D013959:Thyroid Diseases / Q000235:genetics / Q000378:metabolism; D056825:Thyroxine-Binding Globulin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D056825:Thyroxine-Binding Globulin