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FSHß Gene Mutations in a Female with Partial Breast Development and a Male Sibling with Normal Puberty and Azoospermia

Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology (L.C.L.), and Neurobiology Program (L.C.L.), The Institute of Molecular Medicine and Genetics, The Medical College of Georgia, Augusta, Georgia 30912; Section of Endocrinology (A.L.A.P., L.A.C.R.d.M.), Department of Medicine, University of Brasilia, Brasilia 71525, DF, Brazil; Abbott Pharmaceutical Company (J.X.), Abbott Park, Illinois 60664; Section of Reproductive Endocrinology (L.D.C.d.M.), Department of Obstetrics and Gynecology, University of Brasilia, Brasilia, DF, Brazil; Serono (W.W.), Rockland, Massachusetts 02370; and Reproductive Endocrine Laboratory Unit (P.M.S.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Lawrence C. Layman, M.D., Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, The Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912-3360. E-mail: . Llayman{at}mail.mcg.edu

Abstract

FSH is a dimeric pituitary glycoprotein hormone that regulates gonadal function. Human mutations in the FSHß gene have been shown to produce complete deficiency states in which pubertal development and reproductive capacity are inhibited. To date, no patients with partial or complete pubertal development due to FSHß mutations have been documented in humans. We describe and characterize affected siblings, a male and a female, with evidence of pubertal development due to homozygosity for a Tyr76X nonsense mutation in the FSHß gene. In vitro analysis of this mutant demonstrates unmeasurable FSH by immunoassay and by two different bioassays, using either cAMP (homologous FSH bioassay) or estradiol (rat granulosa cell assay) as the endpoints. In additional in vitro analyses, mutants previously found in patients with a phenotype of complete FSH deficiency (Cys51Gly and Val61X) and the Tyr76X were compared in the same immuno- and bioassays. All mutations failed to produce measurable FSH by all assays. Unexpectedly, these siblings with isolated FSH deficiency due to a nonsense FSHß mutation had some evidence of puberty, suggesting that other factors might preserve gonadal steroidogenesis in the absence of FSH or that current bioassays cannot discriminate among very low FSH levels.

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