Journal
HUMAN MOLECULAR GENETICS
Volume 27, Issue 2, Pages 359-372Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx408
Keywords
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Funding
- Swiss National Science Foundation [310030_173260]
- Bourse de Recherche en Endocrinologie SFE
- Institut National de la Sante et de la Recherche Medicale, INSERM, France [U1172]
- Agence Nationale de la Recherche, ANR, France [ANR-14-CE12-0015-01 RoSes]
- Agence Nationale de la Recherche, ANR, France (GnRH)
- Swiss National Science Foundation (SNF) [310030_173260] Funding Source: Swiss National Science Foundation (SNF)
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Congenital hypogonadotropic hypogonadism(CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), aremutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotesmigration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons inmice.
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