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

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.

SUBMITTER: Xu N 

PROVIDER: S-EPMC3888818 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature