Deciphering genetic disease in the genomic era: the model of GnRH deficiency

Abstract

Isolated gonadotropin-releasing hormone (GnRH) deficiency is a treatable albeit rare form of reproductive failure that has revealed physiological mechanisms controlling human reproduction, but despite substantial progress in discovering pathogenic single-gene defects, most of the genetic basis of GnRH deficiency remains uncharted. Although unbiased genetic investigations of affected families have identified mutations in previously unsuspected genes as causes of this disease in some cases, their application has been severely limited because of the negative effect of GnRH deficiency on fertility; moreover, relatively few of the many candidate genes nominated because of biological plausibility from in vitro or animal model experiments were subsequently validated in patients. With the advent of exciting technological platforms for sequencing, homozygosity mapping, and detection of structural variation at the whole-genome level, human investigations are again assuming the leading role for gene discovery. Using human GnRH deficiency as a paradigm and presenting original data from the screening of numerous candidate genes, we discuss the emerging model of patient-focused clinical genetic research and its complementarities with basic approaches in the near future.

Fig. 1

Genes mutated in IHH have critical roles in GnRH neuron ontogeny and physiology. See the text for details. KAL1, Kallmann syndrome 1 sequence, MIM: 308700; FGFR1, fibroblast growth factor receptor 1, MIM: 136350; FGF8, fibroblast growth factor 8, MIM: 600483; PROK2, prokineticin 2, MIM: 607002; PROKR2, prokineticin receptor 2, MIM: 607123; CHD7, chromodomain helicase DNA binding protein 7, MIM: 608765; NELF, nasal embryonic LHRH factor, MIM: 608137; DAX1, dosage-sensitive sex reversal, adrenal hypoplasia congenital (AHC) critical region on the X chromosome, gene 1, MIM: 300473; PC1, prohormone convertase 1, MIM: 162150; LEP, leptin, MIM: 164160; LEPR, leptin receptor, MIM: 601007; KISS1R, KISS1 receptor, MIM: 604161; TAC3, tachykinin 3, MIM: 162330; TACR3, tachykinin receptor 3, MIM: 162332; GNRH1, gonadotropin-releasing hormone 1, MIM: 152760; GNRHR, GnRH receptor, MIM: 138850. CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE

Fig. 2

Timeline of IHH gene discovery. CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE

Fig. 3

Changing models of clinical genetic research. CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE