Examination of reproductive aging milestones among women who carry the FMR1 premutation.
BACKGROUND
The fragile X premutation is characterized by a large CGG repeat track (55-199 repeats) in the 5' UTR of the FMR1 gene. This X-linked mutation leads to an increased risk for premature ovarian failure; interestingly, the association of repeat size with risk is non-linear. We hypothesize that the premutation-associated ovarian insufficiency is due to a diminished oocyte pool and examined reproductive aging milestones by repeat size group to determine if the same non-linear association is observed.


METHODS
We analyzed cross-sectional reproductive history questionnaire data from 948 women with a wide range of repeat sizes.


RESULTS
We have confirmed the non-linear relationship among premutation carriers for ovarian insufficiency. The mid-range repeat size group (80-100 repeats), not the highest group, had an increased risk for: altered cycle traits (shortened cycle length, irregular cycles and skipped cycles), subfertility and dizygotic twinning. Smoking, a modifiable risk, decreased the reproductive lifespan of women with the premutation by about 1 year, similar to its effect on non-carriers. As expected, premutation carriers were found to be at an increased risk for osteoporosis.


CONCLUSIONS
Possible molecular mechanisms to explain the non-linear repeat size risk for ovarian insufficiency are discussed.
Allen
E G
EG
Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA. egraves@genetics.emory.edu
Sullivan
A K
AK
Marcus
M
M
Small
C
C
Dominguez
C
C
Epstein
M P
MP
Charen
K
K
He
W
W
Taylor
K C
KC
Sherman
S L
SL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008597:Menstrual Cycle; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000453:epidemiology; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D012098:Reproduction / Q000502:physiology*; D012907:Smoking / Q000503:physiopathology; D014429:Twins, Dizygotic
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human