Karla Bretherick
KARLA LUCIA BRETHERICK- PhD DEFENSE PROGRAMME
B.Sc. Cellular Molecular & Microbial Biology, University
of Calgary, 2000
Monday, April 7, 2008, 9:00 am Room 200, Graduate Student
Centre
“Genetic
Factors in Premature Ovarian Failure”
EXAMINING
COMMITTEE
Chair: Dr. Basil
Ho Yuen (Reproductive and Developmental Science)
Supervisory
Committee: Dr. Wendy Robinson, Research Supervisor (Medical Genetics) &
Dr. Carolyn Brown (Medical Genetics)
University
Examiners: Dr. Dan Rurak (Obstetrics and Gynecology.) Dr. Dixie Mager
(Medical Genetics)
External Examiner: Dr. Stephanie Sherman Department of Human Genetics Emory University Atlanta, Georgia USA
Karla Bretherick- PhD programme (pdf)
ABSTRACT
Approximately 1% of women will experience menopause before the age of 40, a condition known as premature ovarian failure (POF). The goal of this thesis was to identify genetic causes of POF by examining a number of candidate factors in POF patients and control women. Carriers of FMR1 premutations (55-200 CGG repeats) are known to be at increased risk of POF. A higher prevalence of alleles between 35-54 repeats was found among POF patients (p=0.01), suggesting that risk for POF may extend outside the classic premutation range. There was no evidence for any difference in FMR1 promoter methylation or gene expression between cases and controls. Allele distributions of gene polymorphisms in the androgen receptor (AR), estrogen receptor β, sex hormone binding globulin, and FSH receptor genes did not differ between POF patients and controls. However, haplotype at the estrogen receptor α gene, ESR1, was found to be associated with POF in a simple dominant manner (RR=9.7; 95% CI=2.6-35.6). Although the functional effect of this haplotype could not be confirmed, it may confer a more active promoter that influences risk by increasing the rate of follicular atresia. X-chromosome inactivation (XCI) skewing can indicate an abnormal X chromosome and may therefore be increased in POF patients. There was no increase in skewed XCI ≥90% in patients with secondary amenorrhea, however, there was a significant increase in 4 POF patients with primary amenorrhea (p=0.001). No X-chromosome abnormalities were detectable by high resolution DNA microarray, and skewed XCI may be explained by a trisomic rescue event causing reduced follicular pool. Age-related chromosome factors were assessed to determine if POF patients demonstrate an increased rate of cellular aging. With age, XCI skewing and AR methylation increase and telomere length decreases. There was no difference in skewing or methylation between patients and controls. Surprisingly telomere length was increased in POF patients (p=0.04), a finding that may be explained by abnormal estrogen exposure. Genotype at the longevity-associated APOE gene was not associated with POF. In conclusion, these findings have illuminated several new areas of research in this field and provide background for future research into POF pathogenesis.
PUBLICATIONS
Bretherick KL, Hanna CW, Currie LM, Fluker MR, Hammond GL,
Robinson WP (2007). Survey of endocrine relate gene variants reveals that
estrogen receptor α polymorphisms are associated with idiopathic premature
ovarian failure. Fertility and Sterility 89(2):318-24.
Bretherick KL, Metzger DL, Chanoine JP, Panagiotopoulos C,
Watson SK, Lam WL, Fluker MR, Brown CJ, Robinson WP (2007). Skewed X-chromosome
inactivation is associated with primary but not secondary ovarian failure.
American Journal of Medical Genetics A 143(9):945-51.
Bretherick KL, Fluker MR, Robinson WP (2005). FMR1 repeat
sizes in the grey zone and high end of the normal range are associated with
premature ovarian failure. Human Genetics 117(4):276-282.
Bretherick KL, Gair JL, Robinson WP (2005). The association of skewed X- chromosome inactivation with aneuploidy in humans. Cytogenetic and Genome Research 111(3-4):260-265.
PRESENTATIONS
Hanna CW, Bretherick
KL,Gair JL, Stephenson MD, Brown CJ, Lansdorp PM,
Bretherick
KL, Hanna CW, Fluker MR, Robinson WP (2007). Telomere length
is
Hanna CW, Bretherick
KL, Gair JL, Stephenson M, Robinson WP (2007). Telomere length and skewed
XCI in mothers of a trisomic pregnancy. American Society of Human Genetics 57th
Annual Meeting, San Diego, Oct 23-27, 2007.
Bretherick
KL, FLuker MR, Robinson WP (2007). FMR1 expression is not
altered in premature ovarian failure patients who lack a premutation allele.
13th International Workshop on Fragile X and X-Linked Mental Retardation,
Venice, Oct 3-7, 2007.
Bretherick
KL, Fairbrother N, Harbord SH, Avila L, Robinson WP (2006).
Fertility 101: A survey of university women’s knowledge of reproductive ageing.
Canadian Fertility & Andrology Society 52nd Annual Meeting, Ottawa, Nov
15-18, 2006.
Bretherick
KL, Fluker MR, Brown CJ, Robinson WP (2006). X chromosome DNA
methylation: a new quantitative assay and preliminary results in women with
premature ovarian failure. American Society of Human Genetics 56th Annual
Meeting, New Orleans, Oct 9-13, 2006.
Bretherick
KL, Currie LM, Fluker MR, Robinson WP (2005). Estrogen
receptor polymorphisms and premature ovarian failure. American Society of Human
Genetics 55th Annual Meeting, Salt Lake City, Oct 25-29, 2005.
Bretherick
KL, Fluker MR, Robinson WP (2005). Hormone receptor variants
and premature ovarian failure. European Human Genetics Conference, Prague, May
7-10, 2005.
Bretherick
KL, Fluker MR, Stephenson M, Robinson WP (2004). FMR1 repeat
length in premature ovarian failure and mothers of trisomy. American Society of
Human Genetics 54th Annual Meeting, Toronto, Oct 26-30, 2004.
Bretherick KL, Fluker MR, Beever CL, Anderson CL, Brown CJ, Robinson WP (2003). Skewed X chromosome inactivation in premature ovarian failure. American Society of Human Genetics 53rd Annual Meeting, Los Angeles, Nov 4-8, 2003.
GRADUATE
STUDIES
Field of
Study: Genetics and Women’s Reproductive Health
Courses
MEDG520: Advanced Human Molecular Genetics, Dr. E. Simpson
MEDG530: Human Genetics, Dr. J. Friedman
MEDG540: Seminar, Dr. F. Dill
MEDG545: Current Topics in Medical Genetics, Dr. C. Brown
MEDG548: Directed Studies, Dr. W. Robinson
INDS502: Ethics of Research Involving Humans, Dr. M.
McDonald
AWARDS
CIHR Institute of Gender and Health, Doctoral Research Award
Michael Smith Foundation for Health Research, Senior Graduate
Scholarship
UBC Medical Genetics, James Miller Award
Interdisciplinary Women’s Reproductive Health Training
Program, Studentship
CIHR Institute of Genetics, Doctoral Research Award
Michael Smith Foundation for Health Research, Junior
Graduate Scholarship
Natural Science and Engineering Research Council,
Postgraduate Scholarship A
SUPERVISORY
COMMITTEE
Dr. Wendy Robinson (Medical Genetics)
Dr. Carolyn Brown (Medical Genetics)
Dr. Geoff Hammond (Obstetrics and Gynecology)
Dr. Barbara McGillivray (Medical Genetics)
Karla Bretherick- PhD programme (pdf)