Journal article
Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy
American journal of human genetics, Vol.99(2), pp.423-429
08/04/2016
DOI: 10.1016/j.ajhg.2016.05.031
PMCID: PMC4974069
PMID: 27453577
Abstract
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.
Details
- Title: Subtitle
- Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy
- Creators
- Michael S Hildebrand - Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, AustraliaNicole G Griffin - Institute for Genomic Medicine, Columbia University, New York, NY 10032, USAJohn A Damiano - Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, AustraliaElisa J Cops - Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, AustraliaRosemary Burgess - Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, AustraliaEzgi Ozturk - Department of Medicine, The University of Melbourne and The Royal Melbourne Hospital, Parkville, VIC 3050, AustraliaNigel C Jones - Department of Medicine, The University of Melbourne and The Royal Melbourne Hospital, Parkville, VIC 3050, AustraliaRichard J Leventer - Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne and The Royal Children's Hospital, Parkville, VIC 3052, Australia; Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, AustraliaJeremy L Freeman - Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, AustraliaA Simon Harvey - Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne and The Royal Children's Hospital, Parkville, VIC 3052, Australia; Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, AustraliaLynette G Sadleir - Department of Paediatrics and Child Health, University of Otago, Wellington 9016, New ZealandIngrid E Scheffer - Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia; Department of Paediatrics, University of Melbourne and The Royal Children's Hospital, Parkville, VIC 3052, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, AustraliaHeather Major - Department of Pediatrics, The University of Iowa, Iowa City, IA 52246, USABenjamin W Darbro - Department of Pediatrics, The University of Iowa, Iowa City, IA 52246, USAAndrew S Allen - Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USADavid B Goldstein - Institute for Genomic Medicine, Columbia University, New York, NY 10032, USAJohn F Kerrigan - Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85013, USASamuel F Berkovic - Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia. Electronic address: s.berkovic@unimelb.edu.auErin L Heinzen - Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: eh2682@cumc.columbia.edu
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.99(2), pp.423-429
- DOI
- 10.1016/j.ajhg.2016.05.031
- PMID
- 27453577
- PMCID
- PMC4974069
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- R21 NS078657 / NINDS NIH HHS
- Language
- English
- Date published
- 08/04/2016
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984093470302771
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