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Fertil Steril. 2011 Apr;95(5):1613-20.e1-7. doi: 10.1016/j.fertnstert.2011.01.010. Epub 2011 Feb 15.

Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.

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  • 1Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912, USA.

Abstract

OBJECTIVE:

To determine if mutations in NELF, a gene isolated from migratory GnRH neurons, cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS).

DESIGN:

Molecular analysis correlated with phenotype.

SETTING:

Academic medical center.

PATIENT(S):

A total of 168 IHH/KS patients as well as unrelated control subjects were studied for NELF mutations.

INTERVENTION(S):

NELF coding regions/splice junctions were subjected to polymerase chain reaction (PCR)-based DNA sequencing. Eleven additional IHH/KS genes were sequenced in three patients with NELF mutations.

MAIN OUTCOME MEASURE(S):

Mutations were confirmed by sorting intolerant from tolerant, reverse-transcription (RT)-PCR, and Western blot analysis.

RESULT(S):

Three novel NELF mutations absent in 372 ethnically matched control subjects were identified in 3/168 (1.8%) IHH/KS patients. One IHH patient had compound heterozygous NELF mutations (c.629-21G>C and c.629-23C>G), and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c.1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). In vitro evidence of these NELF mutations included reduced protein expression and splicing defects.

CONCLUSION(S):

Our findings suggest that NELF is associated with normosmic IHH and KS, either singly or in combination with a mutation in another gene.

Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

PMID:
21300340
[PubMed - indexed for MEDLINE]
PMCID:
PMC3888818
Free PMC Article
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