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The Frequency of an Inactivating Point Mutation (⁵⁶⁶CT) of the Human Follicle-Stimulating Hormone Receptor Gene in Four Populations Using Allele-Specific Hybridization and Time-Resolved Fluorometry¹

Departments of Physiology (M.J., P.P., I.H.) and Biotechnology (C.N., A.I., K.P.), University of Turku, 20520 Turku; the Department of Clinical Genetics, Helsinki University Central Hospital (K.A.), 00029 Helsinki; and Folkhälson Institute of Genetics (A.d.I.C.), 00280 Helsinki, Finland; the Division of Endocrinology (T.T.), University Children’s Hospital, CH-8032 Zurich, Switzerland; the Department of Clinical Biochemistry (H.S.), Statens Serum Institute, 2300 Copenhagen, Denmark; the Department of Obstetrics and Gynecology, National University of Singapore (V.G.), 119074 Singapore; and the Comprehensive Cancer Center, Ohio State University (A.d.l.C.), Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Prof. Ilpo T. Huhtaniemi, Department of Physiology, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. E-mail: ilpo.huhtaniemi{at}utu.fi

We have described previously in the Finnish population an inactivating point mutation (⁵⁶⁶CT) in the human FSH receptor (FSHR) gene. In women, this mutation causes hypergonadotropic ovarian failure with arrest of follicular maturation and infertility, whereas in men, there is variable suppression of spermatogenesis, but no absolute infertility. To determine whether the same FSHR mutation occurs in other populations, its frequency was determined in Finland, Switzerland, Denmark, and the Chinese population of Singapore. The mutation was screened for using genomic DNA extracted from whole blood or dried blood spots. Exon 7 of the FSHR gene was first amplified using a pair of biotinylated primers. The PCR products were then immobilized on streptavidin-coated microtitration wells and hybridized using short allele-specific oligonucleotide probes labeled with europium. Time-resolved fluorometry was used for europium signal detection. To test the reliability of this method, 40 isolated DNA samples and 35 dried blood spot samples were blindly tested for the ⁵⁶⁶CT FSHR mutation. The analyses yielded identical results with denaturing gradient gel electrophoresis and allele-specific restriction enzyme digestion of the same samples, thus demonstrating the reliability of the tested method. Automation of this procedure allows the screening of large numbers of samples, which was subsequently carried out to investigate the frequency of the ⁵⁶⁶CT mutation in the study populations. A total of 4981 samples from the above-mentioned 4 countries were analyzed. The frequency of the ⁵⁶⁶CT mutation was 0.96% for all Finnish samples (n = 1976), with a strong enrichment of the mutant allele in the northeastern part of the country. Only 1 mutation carrier was identified in the samples from Switzerland (n = 1162), whereas none was found in samples from Denmark (n = 1094) and the Singapore Chinese (n = 540). These results suggest that the ⁵⁶⁶CT mutation of the FSHR gene is enriched in Finland, but is uncommon in other populations.

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