Molecular genetics of epilepsy and mental retardation limited to females (EFMR).
Date
2010
Authors
Hynes, Kim Elizabeth
Editors
Advisors
Gecz, Jozef
Mulley, John Charles
Mulley, John Charles
Journal Title
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Type:
Thesis
Citation
Statement of Responsibility
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Abstract
Epilepsy and mental retardation limited to females (EFMR) is an intriguing X-linked disorder, which exhibits counterintuitive sex specific phenotype presentation, with heterozygous females affected and hemizygous males spared. Affected females suffer from epilepsy, which typically begins prior to three years of age. Onset of seizures often coincides with developmental regression resulting in intellectual disability.
• Using high throughput sequencing of the X-chromosome we have identified 7 different mutations in protoccadherin-19 (PCDH19) in 7 families with EFMR (Dibbens et al., 2008), including the original EFMR family published in 1971 (Juberg and Hellman, 1971). The discovery of mutations in PCDH19, a calcium cell-cell adhesion molecule, in EFMR highlights protocadherins and cell adhesion molecules in general, as a novel class of genes involved in intellectual disability and epilepsy. Publication 1, appendix A, (Dibbens et al., 2008)
• We have conducted follow up screening in three additional cohorts and identified additional mutations in the PCDH19 gene in smaller families and a sporadic case with EFMR. PCDH19 was not found to be a major cause of Rett syndrome or Autism Spectrum Disorder alone. Publication 2, appendix B, (Hynes et al., 2009)
• We have also identified an additional, large, black Afro-American family with EFMR with a missense mutation in PCDH19 that is predicted to result in loss of function of PCDH19 protein. (Publication in preparation).
• We have performed genome-wide microarray expression profiling analyses and identified altered expression of genes involved in axon guidance and cell migration in EFMR females. We also unexpectedly found that EFMR females had a “male-like” expression profile of more than 100 genes and altered expression of 10 genes which function in aspects of estrogen production, activation and degradation or that are known downstream targets of estrogen. This suggests that response to estrogen may be disrupted in certain cells. (Publication in preparation).
• Through genome-wide microarray expression profiling analyses we also identified altered expression of 13 genes involved in the Ephrin / Eph signalling pathway in EFMR females. The altered expression of Ephrin / Eph signalling genes and the parallels identified between EFMR and CFNS (craniofrontonasal syndrome), with respect to inheritance pattern, lead us to hypothesise a potential interaction between PCDH19 and Ephrin / Eph signalling.
In conclusion, we have identified the causative gene for EFMR and gained novel insights into additional genes and signalling pathways that are disrupted as a result of mutations in PCDH19 in females.
School/Discipline
School of Molecular and Biomedical Science
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010
Provenance
Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.