CINTIA TUSSET
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- New genetic factors implicated in human GnRH-dependent precocious puberty: The role of kisspeptin system(2011) TELES, Milena Gurgel; SILVEIRA, Leticia Ferreira Gontijo; TUSSET, Cintia; LATRONICO, Ana ClaudiaHuman puberty is triggered by the reemergence of GnRH pulsatile secretion with progressive activation of the gonadal function. A number of genes have been identified in the complex regulatory neuroendocrine network that controls puberty initiation. KISS1 and KISS1R genes, which encode kisspeptin and its cognate receptor, respectively, are considered crucial factors for acquisition of normal reproductive function. Recently, rare missense mutations and single nucleotide polymorphisms (SNPs) of the kisspeptin system were associated with puberty onset. Two gain-of-function mutations of the KISS1 and KISS1R genes were implicated in the pathogenesis of GnRH-dependent precocious puberty, previously considered idiopathic. These discoveries have yielded significant insights into the physiology and pathophysiology of this important life transition time. Here, we review the current molecular defects that are implicated in human GnRH-dependent precocious puberty.
- TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients(2014) NOEL, Sekoni D.; ABREU, Ana Paula; XU, Shuyun; MUYIDE, Titilayo; GIANETTI, Elena; TUSSET, Cintia; CARROLL, Jessica; LATRONICO, Ana Claudia; SEMINARA, Stephanie B.; CARROLL, Rona S.; KAISER, Ursula B.Neurokinin B (NKB) and its G-protein-coupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, little is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans. Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3 +/- 7.2%) or plasma membrane (67.3 +/- 7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability. We further demonstrate in a FRET-based assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of G(q)-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 +/- 1.3% reduction in FRET ratios following ligand binding, indicating activation of G(q)-protein signaling. Interestingly, R295S NK3R, identified in the heterozygous state in a GnRH-deficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.-Noel, S. D., Abreu, A. P., Xu, S., Muyide, T., Gianetti, E., Tusset, C., Carroll, J., Latronico, A. C., Seminara, S. B., Carroll, R. S., Kaiser, U. B. TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients.