2. Academic Validation
  3. TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci

TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci

  • Hum Mol Genet. 2020 Aug 11;29(14):2435-2450. doi: 10.1093/hmg/ddaa120.
Erica E Davis 1 2 3,  Ravikumar Balasubramanian 4 5,  Zachary A Kupchinsky 1,  David L Keefe 4,  Lacey Plummer 4,  Kamal Khan 2 3,  Blazej Meczekalski 6,  Karen E Heath 7,  Vanesa Lopez-Gonzalez 8,  Mary J Ballesta-Martinez 8,  Gomathi Margabanthu 9,  Susan Price 10,  James Greening 11,  Raja Brauner 12,  Irene Valenzuela 13 14,  Ivon Cusco 13 14,  Paula Fernandez-Alvarez 13 14,  Margaret E Wierman 15,  Taibo Li 16 17 18,  Kasper Lage 5 16 17,  Priscila Sales Barroso 19,  Yee-Ming Chan 20,  William F Crowley 5 21,  Nicholas Katsanis 1 2 3
Affiliations

Affiliations

  • 1 Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
  • 2 Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 3 Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 4 Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital (MGH), Boston, MA 02114, USA.
  • 5 Harvard Medical School, Boston, MA 02115, USA.
  • 6 Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-512 Poznan, Poland.
  • 7 Institute of Medical and Molecular Genetics (INGEMM) Hospital Universitario La Paz, Universidad Autonoma de Madrid, IdiPAZ, Madrid, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28046 Madrid, Spain.
  • 8 Medical Genetics Unit, Department of Pediatrics, Hospital Clinico, Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain and CIBERER, ISCIII, 28046 Madrid, Spain.
  • 9 Kettering General Hospital, Kettering, Northamptonshire NN16 8UZ, UK.
  • 10 Northampton General Hospital, Northampton NN1 5BD, UK.
  • 11 University Hospitals of Leicester, Leicester LE3 9QP, UK.
  • 12 Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, 75019 Paris, France.
  • 13 Department of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
  • 14 Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
  • 15 Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 16 Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 17 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 18 Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
  • 19 Divisao de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, 05403-900 Brazil.
  • 20 Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 21 MGH Center for Human Genetics & The Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston MA 02114, USA.
PMID: 32620954 DOI: 10.1093/hmg/ddaa120
Abstract

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

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