title: Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure.
abstract: BACKGROUND
  Inactivating FSH receptor (FSHR) mutations can affect ovarian function, resulting in variable clinical presentations ranging from primary amenorrhea to premature menopause. FSHR mutations have been largely reported in the Finnish population, but in patients of Asian Indian descent, the incidence of FSHR mutations is extremely rare.
  
  
  METHODS
  Two female siblings of Indian descent were diagnosed with primary ovarian failure and hypergonadotropic hypogonadism. The daughters were the result of a consanguineous marriage between second cousins. A combination of comparative genomic hybridization plus single nucleotide polymorphism array and whole exome sequencing was conducted on the family to identify potential causative genetic variants.
  
  
  CONCLUSIONS
  Both daughters were found to have a novel pathogenic variant in FSHR (c.1253T>G, p.Ile418Ser), inherited as an autosomal recessive trait from heterozygous parents. This loss of function mutation is located in exon 10 of FSHR affecting the second transmembrane helix of the FSHR protein. The transmembrane domain of FSHR is highly conserved across species and is involved in signal transduction. The FSHR c.1253T>G variant is next to a known pathogenic variant, rs12190966 (c.1255G>A, p.Ala419Thr), previously reported in a Finnish woman with primary amenorrhea.
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: S
authors: S
authors: Katari
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: M A
authors: MA
authors: Wood-Trageser
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: H
authors: H
authors: Jiang
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: E
authors: E
authors: Kalynchuk
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: R
authors: R
authors: Muzumdar
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: S A
authors: SA
authors: Yatsenko
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences (S.K., M.A.W.-T., H.J., S.A.Y., A.R.), Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213; Department of Pathology (A.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Endocrinology (R.M.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; and Department of Human Genetics (E.K., S.A.Y., A.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors: A
authors: A
authors: Rajkovic
mesh_terms: D000293:Adolescent; D003241:Consanguinity; D005260:Female; D006801:Humans; D007194:India; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011962:Receptors, FSH / Q000235:genetics*; D035781:Siblings
chemical_list: D011962:Receptors, FSH