title: Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.
abstract: OBJECTIVE
  Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG.
  
  
  METHODS
  Because consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families.
  
  
  METHODS
  Hundred and thirty-nine children with CHNG phenotype born to consanguineous families.
  
  
  METHODS
  First, we investigated cases for evidence of linkage to the four known CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition, in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation-specific disease phenotype.
  
  
  RESULTS
  Homozygous germline TSHR mutations were detected in six families (5%), but no mutations were detected in PAX8, TSHB and NKX2-5. Four of TSHR mutations had not previously been described. Genotype-phenotype correlations were established and found to be related to the predicted structural effects of the mutations.
  
  
  CONCLUSIONS
  Known causative genes account for the development of CHNG only in a minority of cases, and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG.
authors: Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. h.cangul@bham.ac.uk
authors: Hakan
authors: H
authors: Cangul
authors: Neil V
authors: NV
authors: Morgan
authors: Julia R
authors: JR
authors: Forman
authors: Halil
authors: H
authors: Saglam
authors: Zehra
authors: Z
authors: Aycan
authors: Tahsin
authors: T
authors: Yakut
authors: Tuna
authors: T
authors: Gulten
authors: Omer
authors: O
authors: Tarim
authors: Ece
authors: E
authors: Bober
authors: Yasar
authors: Y
authors: Cesur
authors: Gail A
authors: GA
authors: Kirby
authors: Shanaz
authors: S
authors: Pasha
authors: Mutlu
authors: M
authors: Karkucak
authors: Erdal
authors: E
authors: Eren
authors: Semra
authors: S
authors: Cetinkaya
authors: Veysel
authors: V
authors: Bas
authors: Korcan
authors: K
authors: Demir
authors: Sevil A
authors: SA
authors: Yuca
authors: Esther
authors: E
authors: Meyer
authors: Michaela
authors: M
authors: Kendall
authors: Wolfgang
authors: W
authors: Hogler
authors: Timothy G
authors: TG
authors: Barrett
authors: Eamonn R
authors: ER
authors: Maher
mesh_terms: D003409:Congenital Hypothyroidism / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D010154:Pakistan / Q000208:ethnology; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*; D037322:Thyrotropin, beta Subunit / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014421:Turkey; D006113:United Kingdom
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D011989:Receptors, Thyrotropin; D037322:Thyrotropin, beta Subunit; D014157:Transcription Factors