Section 13
Chapter 12,642

The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice

Jin, R.; Hodges, C.A.; Drumm, M.L.; Palmert, M.R.

Journal of Medical Genetics 43(6): E29


ISSN/ISBN: 1468-6244
PMID: 16740913
DOI: 10.1136/jmg.2005.032839
Accession: 012641676

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Delayed puberty is common among individuals with cystic fibrosis (CF) and is usually attributed to chronic disease and/or poor nutrition. However, it has recently been recognised that pubertal delay can occur even in the setting of good nutritional and clinical status. This finding, along with evidence that Cftr is expressed in rat brain, human hypothalamus, and a gonadotropin releasing hormone secreting cell line, raises the possibility that some of the pubertal delay in CF could stem directly from alterations in Cftr function that affect the hypothalamic-pituitary-gonadal axis. To examine this hypothesis, we investigated pubertal timing (as assessed by vaginal opening (VO)) in a mouse model of CF (Cftr(tm1Unc)) engineered to produce a truncated Cftr mRNA and referred to as S489X. Homozygous knockout, heterozygote, and wild type (WT) female mice were examined. As expected, the S489X-/S489X- knockout mice, which have chronic inflammation and gastrointestinal disease, grew more slowly and had later onset of puberty than WT animals. We anticipated that the S489X-/S489X+ heterozygotes, which have no clinical CF phenotype, might display an intermediate timing of puberty. Surprisingly, however, these mice had earlier VO than WT. These findings were confirmed in a second, independent model of CF engineered to generate the deltaF508 mutation in mice. Again, the homozygotes displayed later pubertal timing, while the heterozygotes displayed earlier VO than the WT animals. These data provide further evidence that Cftr can directly modulate the reproductive endocrine axis and raise the possibility that heterozygote mutation carriers may have a reproductive advantage.

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