title: A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics.
abstract: 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.
  
  
  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.
authors.affiliation: School of Clinical Medical Sciences, University of Newcastle NE2 4HH, UK.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Allen
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Pirjo
authors.initials: P
authors.lastname: Pakarinen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kotlar
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
authors.forename: Tim D
authors.initials: TD
authors.lastname: Cheetham
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ball
mesh_terms: D000293:Adolescent; D000568:Amenorrhea / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D020223:Chromosome Painting; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D011962:Receptors, FSH / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone; D004247:DNA