DNA polymorphisms of the KiSS1 3' untranslated region interfere with the folding of a G-rich sequence into G-quadruplex.

KISS1R and its ligand, the kisspeptins, are key hypothalamic factors that regulate GnRH hypothalamic secretion and therefore the pubertal timing. During studies analysing KiSS1 as a candidate gene in pubertal onset disorders, two SNP and one nucleotide insertion were observed in a 23 nucleotides G-rich sequence located 65 nucleotides downstream of the stop codon. The polymorphisms formed four haplotypes. Biophysical experiments revealed the ability of this G-rich sequence to fold into G-quadruplex structures and demonstrated that the three DNA polymorphisms did not perturb the folding into G-quadruplex but affected G-quadruplex conformation. A functional luciferase reporter-based assay revealed functional differences between 3'UTR haplotypes. These data show that polymorphisms in a G-rich sequence of the 3'UTR of KISS1, able to fold into G-quadruplex structures, can modulate gene expression. They highlight the potential role of this G-quadruplex in the regulation of KISS1 expression and in the timing of pubertal onset.

Predictors of late menarche and adult height in children with anorexia nervosa.

OBJECTIVES: The onset of anorexia nervosa (AN) during childhood can affect the timing of puberty and adult height. The aim of the study was to evaluate the determinants of late menarche and adult height in children with AN. PATIENTS AND METHODS: We carried out a retrospective, longitudinal, university hospital-based study. All prepubertal or early pubertal girls diagnosed with AN between 1998 and 2002 were selected for the study. Participants (n = 33) were studied at a median age of 21 (19.8-24.3) years. AN was diagnosed at 11.8 (10.7-12.3) years. RESULTS: Patients with AN reached menarche at significantly greater ages than their mothers [15.4 (13.5-16.8) vs. 13.2 (12.0-14.5) years, P < 0.01]. Chronological age at onset of AN and lowest body mass index (BMI) were important independent predictive factors for delayed menarche (P < 0.01). Adult height was 165.0 (163.0-172.0) cm, 2.5 (-1.5 to 5.0) cm above target height. Twelve patients (36%) did not reach their target height and had a median height deficit of -3.9 cm with respect to their target height. The duration of hospitalization, a marker of disease severity and chronicity, was an independent predictor of the difference between adult height and target height for a given individual (beta coefficient = -0.07; P = 0.01). The other factors studied (i.e. age at onset of AN, pubertal stage at diagnosis of AN, lowest BMI reached, associated comorbidity if any, type of AN, age at menarche) had no significant effect on adult height. CONCLUSION: The intensity of the disease affects the timing of menarche but not adult height in most patients. Hospitalization, despite often being an effective means of managing AN, does not reduce the impact of AN on growth.