title: Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism.
abstract: BACKGROUND
  Congenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband.
  
  
  METHODS
  We screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband's family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant.
  
  
  RESULTS
  A new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8.
  
  
  CONCLUSIONS
  In vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo.
authors.forename: Monica
authors.initials: M
authors.lastname: Vincenzi
authors.forename: Marta
authors.initials: M
authors.lastname: Camilot
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ferrarini
authors.forename: Francesca
authors.initials: F
authors.lastname: Teofoli
authors.forename: Giacomo
authors.initials: G
authors.lastname: Venturi
authors.forename: Rossella
authors.initials: R
authors.lastname: Gaudino
authors.affiliation: Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy. paolocavarzere@yahoo.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavarzere
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Marco
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agretti
authors.forename: Antonio
authors.initials: A
authors.lastname: Dimida
authors.forename: Massimo
authors.initials: M
authors.lastname: Tonacchera
authors.forename: Attilio
authors.initials: A
authors.lastname: Boner
authors.forename: Franco
authors.initials: F
authors.lastname: Antoniazzi
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000235:genetics; D057809:HEK293 Cells; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000473:pathology; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011989:Receptors, Thyrotropin / Q000235:genetics; D050033:Thyroid Dysgenesis / Q000235:genetics* / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics
chemical_list: D015415:Biomarkers; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D011989:Receptors, Thyrotropin; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors