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Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy.

Publication ,  Journal Article
Hildebrand, MS; Griffin, NG; Damiano, JA; Cops, EJ; Burgess, R; Ozturk, E; Jones, NC; Leventer, RJ; Freeman, JL; Harvey, AS; Sadleir, LG ...
Published in: Am J Hum Genet
August 4, 2016

Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

August 4, 2016

Volume

99

Issue

2

Start / End Page

423 / 429

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli3
  • Zinc Finger Protein Gli2
  • Signal Transduction
  • Nuclear Proteins
  • Nerve Tissue Proteins
  • Mutation
  • Male
  • Loss of Heterozygosity
  • Kruppel-Like Transcription Factors
  • Hypothalamic Diseases
 

Citation

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Hildebrand, M. S., Griffin, N. G., Damiano, J. A., Cops, E. J., Burgess, R., Ozturk, E., … Heinzen, E. L. (2016). Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy. Am J Hum Genet, 99(2), 423–429. https://doi.org/10.1016/j.ajhg.2016.05.031
Hildebrand, Michael S., Nicole G. Griffin, John A. Damiano, Elisa J. Cops, Rosemary Burgess, Ezgi Ozturk, Nigel C. Jones, et al. “Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy.Am J Hum Genet 99, no. 2 (August 4, 2016): 423–29. https://doi.org/10.1016/j.ajhg.2016.05.031.
Hildebrand MS, Griffin NG, Damiano JA, Cops EJ, Burgess R, Ozturk E, et al. Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy. Am J Hum Genet. 2016 Aug 4;99(2):423–9.
Hildebrand, Michael S., et al. “Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy.Am J Hum Genet, vol. 99, no. 2, Aug. 2016, pp. 423–29. Pubmed, doi:10.1016/j.ajhg.2016.05.031.
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):423–429.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

August 4, 2016

Volume

99

Issue

2

Start / End Page

423 / 429

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli3
  • Zinc Finger Protein Gli2
  • Signal Transduction
  • Nuclear Proteins
  • Nerve Tissue Proteins
  • Mutation
  • Male
  • Loss of Heterozygosity
  • Kruppel-Like Transcription Factors
  • Hypothalamic Diseases