Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 191

precocious sexual development [ 75 ]. Hypothalamic hamartomas associated with
CPP were larger than those not associated with CPP and were more likely to contact
the infundibulum or tuber cinereum. However, the expression of KISS1 and KISS1R
was similar in both groups, demonstrating that expression of this signaling pathway
does not differentiate between hamartomas associated with precocity vs. hamarto-
mas that are identifi ed in the setting of normal pubertal development [ 75 ].
Conclusions
Mutations in genes associated with IHH have been identifi ed in approximately
30-40% of the patients with GnRH defi ciency. Although mutations in KISS1 / KISS1R
are not a common cause of hypogonadotropism or CPP, the discovery of defects in
this pathway in IHH as well as in CPP has shed some light on the mechanisms
involved in GnRH secretion regulation, revealing the critical role played by the
kisspeptin signaling pathway in pubertal initiation and reproductive function.
Considering the low incidence of mutations in these genes in precocious puberty
so far, other genes involved in the HPG axis modulation, particularly factors
upstream from, the KISS1 / KiSS1R systems, might be involved in CPP pathogenesis.
New methodologies, such as next generation sequencing and comparative genomic
hybridization (CGH), will provide a more comprehensive assessment of genomic
abnormalities and allow new genes to be uncovered.
Acknowledgments Dr. Seminara and some of the data referenced in this article were supported
by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement [U54 HD028138] as
part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research, as
well as R01 HD043341 and K24 HD067388.
References
1. Crowley WF Jr, McArthur JW (1980) Simulation of the normal menstrual cycle in Kallman's
syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH).
J Clin Endocrinol Metab 51:173-175
2. Hoffman AR, Crowley WF Jr (1982) Induction of puberty in men by long-term pulsatile
administration of low-dose gonadotropin-releasing hormone. N Engl J Med 307:1237-1241
3. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E (2003) Hypogonadotropic
hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl
Acad Sci U S A 100:10972-10976
4. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas
Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA,
Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH (2003) The
GPR54 gene as a regulator of puberty. N Engl J Med 349:1614-1627
5. Maquat LE, Carmichael GG (2001) Quality control of mRNA function. Cell 104:173-176
6. Frischmeyer PA, van Hoof A, O'Donnell K, Guerrerio AL, Parker R, Dietz HC (2002) An
mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science
295:2258-2261