Consecutive Mutational Events in a TSHR Allele of Arab Families with Resistance to Thyroid Stimulating Hormone
Year: 2012
Type: article
Abstract: BACKGROUND: Our laboratory identified six distinct inactivating TSHR gene mutations in Arab tribes living in Israel. We recently reported three nucleotide substitutions in exon 3 producing p.[L89L;Q90P] and one in exon 9 of the same allele producing p.P264S in Family A. Family B, reported herein, harbors the identical mutation in exon 3 only. We set to determine whether the mutations have common ancestral origin. METHODS: Coding regions of the TSHR were sequenced and flanking microsatellite markers spanning 5.3 cM were used for haplotyping. RESULTS: Two siblings of Family B were compound heterozygous for TSHR gene mutations. The paternal allele contained the exon 3 mutation and the maternal allele harbored a mutation in exon 10 (p.L653V). We investigated the possibility of a founder effect with subsequent mutational events for the presence of the same exon 3 mutation in different families. The haplotype of the allele harboring the exon 3 mutation in Family B was identical to that of Family A, also harboring the exon 9 mutation on the same allele, indicating that the latter occurred subsequently. The ancestral wild-type TSHR was present in Family B, suggesting that the mutation in exon 3 was also new in the history of that population. CONCLUSIONS: It is more likely that two consecutive mutational events occurred on the ancestral wild-type allele instead of a recombination bringing exon 3 and exon 9 mutations together on the same allele. New mutational events contribute to the high prevalence of TSHR mutations in this population in addition to a founder effect and limited gene pool due to inbreeding.
Source: Thyroid
Institutions: University of Chicago, Clalit Health Services
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2001195338