ReviewState-of-the-field: Isolated gonadotropin-releasing hormone deficiency

Deciphering Genetic Disease in the Genomic Era: The Model of GnRH Deficiency

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Science Translational Medicine  19 May 2010:
Vol. 2, Issue 32, pp. 32rv2
DOI: 10.1126/scitranslmed.3000288

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In Pursuit of Genetic Roots

The American jazz vocalist “Little” Jimmy Scott is known for his high contralto voice—and also lacks a sense of smell. These seemingly disparate characteristics are the result of Kallmann syndrome, a rare genetic disorder in which there is an isolated deficiency of gonadotropin-releasing hormone (GnRH). Normally, GnRH is secreted during puberty by specialized neurons in the hypothalamus, triggering cells in the pituitary gland to produce hormones that stimulate production of sex steroids, which in turn promote skeletal growth, secondary sexual characteristics, and fertility. GnRH biology can be disrupted at numerous points, causing reproductive failure and, at times, other characteristics. In some cases of Kallmann syndrome, for example, mutations in a certain gene prevent the olfactory tract from forming correctly; precursors of GnRH neurons normally migrate along this structure to the hypothalamus. Thus, both the ability to smell and the development of GnRH-driven characteristics are affected. Despite mutations in 16 genes being linked to isolated GnRH deficiency, most of the genetic basis of this disorder remains to be discovered. Sykiotis and colleagues review the historical path of gene discovery for GnRH deficiency, present their results from the screening of numerous candidate genes, and describe the emerging model of patient-driven gene discovery—a paradigm for uncovering the roots of complex genetic disease in general.


  • * For the Gene Discovery Team of the Harvard Reproductive Endocrine Sciences Center. The Gene Discovery Team also includes Margaret Au, Magdalena Avbelj, Ravikumar Balasubramanian, Yee-Ming Chan, Andrew Dwyer, Elena Gianetti, Adelaide de Guillebon, James F. Gusella, Virginia Hughes, Cecilia Martin, and Lacey Plummer.

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