Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism
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Locate full-text(opens in a new window)| Export | Download | Add to List | More... Journal of Clinical Endocrinology and Metabolism Volume 100, Issue 5, 1 May 2015, Pages E808-E814 Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism (Article) Bayram, Y.a, Gulsuner, S.b, Guran, T.c, Abaci, A.d, Yesil, G.e, Gulsuner, H.U.b, Atay, Z.c, Pierce, S.B.b, Gambin, T.a, Lee, M.b, Turan, S.c, Bober, E.d, Atik, M.M.a, Walsh, T.b, Karaca, E.a, Pehlivan, D.a, Jhangiani, S.N.f, Muzny, D.f, Bereket, A.c, Buyukgebiz, A.d, Boerwinkle, E.fg, Gibbs, R.A.f, King, M.-C.b , Lupski, J.R.ahi a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States b Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, United States c Department of Pediatric Endocrinology and Diabetes, Marmara University Hospital, Istanbul, Turkey d Department of Pediatric Endocrinology, Dokuz Eylül University Faculty of Medicine, Izmir, Turkey e Department of Medical Genetics, Bezmialem University, Istanbul, Turkey f Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States g Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, United States h Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States i Texas Children's Hospital, Houston, TX, United States Hide additional affiliations View references (36) Abstract Context: Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function. Objectives: The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families. Design and Participants: Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families. Results: Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs∗4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance. Conclusions: Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism. Copyright © 2015 by the Endocrine Society.