Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.
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.
Cangul
Hakan
H
Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. h.cangul@bham.ac.uk
Morgan
Neil V
NV
Forman
Julia R
JR
Saglam
Halil
H
Aycan
Zehra
Z
Yakut
Tahsin
T
Gulten
Tuna
T
Tarim
Omer
O
Bober
Ece
E
Cesur
Yasar
Y
Kirby
Gail A
GA
Pasha
Shanaz
S
Karkucak
Mutlu
M
Eren
Erdal
E
Cetinkaya
Semra
S
Bas
Veysel
V
Demir
Korcan
K
Yuca
Sevil A
SA
Meyer
Esther
E
Kendall
Michaela
M
Hogler
Wolfgang
W
Barrett
Timothy G
TG
Maher
Eamonn R
ER
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
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