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DLG2 variants in patients with pubertal disorders.
Jee, Youn Hee; Won, Sehoon; Lui, Julian C; Jennings, Melissa; Whalen, Philip; Yue, Shanna; Temnycky, Adrian G; Barnes, Kevin M; Cheetham, Tim; Boden, Matthew G; Radovick, Sally; Quinton, Richard; Leschek, Ellen W; Aguilera, Greti; Yanovski, Jack A; Seminara, Stephanie B; Crowley, William F; Delaney, Angela; Roche, Katherine W; Baron, Jeffrey.
Afiliación
  • Jee YH; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Won S; Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Lui JC; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Jennings M; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Whalen P; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Yue S; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Temnycky AG; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Barnes KM; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Cheetham T; Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle upon Tyne, United Kingdom.
  • Boden MG; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Radovick S; Department of Pediatrics, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
  • Quinton R; Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle upon Tyne, United Kingdom.
  • Leschek EW; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Aguilera G; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Yanovski JA; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Seminara SB; Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Crowley WF; Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Delaney A; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Roche KW; Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Baron J; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. jeffrey.baron@nih.gov.
Genet Med ; 22(8): 1329-1337, 2020 08.
Article en En | MEDLINE | ID: mdl-32341572
PURPOSE: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. METHODS: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. RESULTS: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. CONCLUSION: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hormona Liberadora de Gonadotropina / Hipogonadismo Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hormona Liberadora de Gonadotropina / Hipogonadismo Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos