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

• Published in: Fertility and sterility Vol. 95; no. 5; pp. 1613 - 1620.e7
• Main Authors: Xu, Ning, Kim, Hyung-Goo, Bhagavath, Balasubramanian, Cho, Sung-Gyu, Lee, Jae Ho, Ha, Kyungsoo, Meliciani, Irene, Wenzel, Wolfgang, Podolsky, Robert H., Chorich, Lynn P., Stackhouse, Kathryn A., Grove, Anna M.H., Odom, Lawrence N., Ozata, Metin, Bick, David P., Sherins, Richard J., Kim, Soo-Hyun, Cameron, Richard S., Layman, Lawrence C.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2011; Elsevier
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Case-Control Studies; Endocrinopathies; Female; genes; Genetic Predisposition to Disease; Genome-Wide Association Study; GnRH neuron migration; gonadotropin-releasing hormone; gonadotropin-releasing hormone (GnRH); Gynecology. Andrology. Obstetrics; heterozygosity; Humans; Hypogonadism - complications; Hypogonadism - genetics; hypogonadotropic hypogonadism; Hypothalamus. Hypophysis. Epiphysis (diseases); Internal Medicine; Kallmann syndrome; Kallmann Syndrome - complications; Kallmann Syndrome - genetics; Male; Malformations of the nervous system; Medical sciences; Middle Aged; mutation; Mutation - physiology; Nasal embryonic LHRH factor; Neurology; neurons; Non tumoral diseases. Target tissue resistance. Benign neoplasms; nose; Obstetrics and Gynecology; patients; phenotype; polymerase chain reaction; Polymorphism, Single Nucleotide; protein synthesis; reverse transcription; sequence analysis; sorting; Transcription Factors - genetics; Western blotting; Young Adult; Nasal embryonic LHRH factor; gonadotropin-releasing hormone (GnRH); hypogonadotropic hypogonadism; GnRH neuron migration; Kallmann syndrome; Endocrinopathy; Human; Hypogonadotropic hypogonadism; Nervous system diseases; Embryo; Hypothalamic diseases; Gynecology; Migration; Gonadotropin RH; Nasopharynx; Obstetrics; Genetic disease; Genital diseases; Cerebral disorder; Neuron; Malformation; Nose; Central nervous system disease; ENT disease; Mutation
• ISSN: 0015-0282; 1556-5653; 1556-5653
• DOI: 10.1016/j.fertnstert.2011.01.010

To determine if mutations in NELF, a gene isolated from migratory GnRH neurons, cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). Molecular analysis correlated with phenotype. Academic medical center. A total of 168 IHH/KS patients as well as unrelated control subjects were studied for NELF mutations. 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. Mutations were confirmed by sorting intolerant from tolerant, reverse-transcription (RT)-PCR, and Western blot analysis. 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. Our findings suggest that NELF is associated with normosmic IHH and KS, either singly or in combination with a mutation in another gene.