Somatic Mutations in Hypothalamic Hamartoma

Researcher

Project Details

Hypothalamic hamartomas are rare, benign congenital tumours associated with intractable epilepsy. Recently we have detected somatic mutations in primary hypothalamic hamartoma tissue by exome sequencing small quantities (< 200 ng) of tumour DNA and comparing it to DNA from the subjects’ leukocytes. In fourteen out of 38 unrelated cases (37%) where precious DNA was extracted from surgically resected tissue we found novel somatic mutations in genes from the sonic hedgehog developmental pathway (Figure 3). We are currently interrogating additional cases using whole genome sequencing.

In the presence of SHH, PTCH no longer inhibits SMO from translocating to the membrane, where it inhibits phosphorylation of GLI2/3 by PKA (PRKACA). Full-length GLI2/3 translocates to the nucleus, and together with GLI1 and the transcriptional coactivator CREBBP, promotes transcription of downstream target genes. Adapted from Hildebrand et al 2016 Am J Hum Genet.

Researchers

  • Dr Michael Hildebrand BBiomed Sci, BSc (Hons), PhD - Laboratory Head
  • John Damiano BSc (Hons) - Senior Research Assistant
  • Amelia McGlade BSc (Hons) - Senior Research Assistant
  • Kristin Rigbye, BSc (Hons)
  • Rebekah Stubbs, BSc, Grad Dip - Technical Assistant

Collaborators

  • A/Prof Angela Morgan, Murdoch Children's Research Institute
  • Prof Melanie Bahlo, Walter and Eliza Hall Institute
  • Prof Patrick Kwan, Royal Melbourne Hospital
  • A/Prof Heather Mefford, University of Washington

Funding

  1. National Health and Medical Research Council (NHMRC) Project Grant APP1129054 2017-2020, Detection of Somatic Mutations in Sporadic Epilepsies, Epilepsy Research Centre, University of Melbourne, Australia ($1,256,165 AUD) CIA: Prof. Samuel F Berkovic, CIB: Dr. Michael S Hildebrand, CIC: Dr. Slave Petrovski, CID: Dr. Snezana Maljevic
  2. National Health and Medical Research Council (NHMRC) Project Grant APP1079058 2015-2017, Exploring somatic mutation in focal epilepsies, Epilepsy Research Centre and Royal Melbourne Hospital, University of Melbourne, Australia, and University of Washington, Seattle, USA ($684,492 AUD) CIA: Dr. Michael S Hildebrand, CIB: Assist. Prof. Heather C. Mefford, CIC: Prof. Patrick Kwan.

Research Publications

  1. Hildebrand MS, Griffin NG, Damiano JA, Cops EJ, Burgess R, Ozturk E, Jones NC, Leventer RJ, Freeman JL, Harvey AS, Sadleir LG, Scheffer IE, Major H, Darbro BW, Allen AS, Goldstein DB, Kerrigan JF, Berkovic SF, Heinzen EL. Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy. Am J Hum Genet. 2016 Aug 4;99(2):423-9.

Research Group

Translational Neurogenetics Laboratory


Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Medicine and Radiology

Unit / Centre

Translational Neurogenetics Laboratory

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