Human Reproduction, Vol. 18, No. 2, 251-256,
February 2003
© 2003 European Society of Human Reproduction and Embryology
A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics
1 School of Clinical Medical Sciences, University of Newcastle NE2 4HH, UK, 2 Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611, USA, 3 Centre for Human Growth and Maturation, Department of Medicine and Institute of Child Health, University College London, London WC1N 1EH, UK and 4 Department of Physiology, University of Turku, Turku, FIN-20520, Finland
5 To whom correspondence should be addressed at: Department of Paediatrics, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. e-mail: t.d.cheetham{at}ncl.ac.uk
BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.
Key words: FSH/FSH receptor/infertility/ovary/puberty
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