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.
INSERM, U676, Hôpital Robert-Debré, 75935 Paris Cedex 19, France; Paris Diderot University, 75018 Paris, France.
Lukas
L
Huijbregts
Catherine
C
Roze
Giulia
G
Bonafe
Muriel
M
Houang
Yves
Y
Le Bouc
Jean-Claude
JC
Carel
Juliane
J
Leger
Patrizia
P
Alberti
Nicolas
N
de Roux
D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000235:genetics*; D005260:Female; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D006801:Humans; D059648:Kisspeptins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide; D011627:Puberty / Q000235:genetics; D055815:Young Adult
D020413:3' Untranslated Regions; C106628:KISS1 protein, human; D059648:Kisspeptins; D004247:DNA