Alternative titles; symbols
HGNC Approved Gene Symbol: NSMF
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38) : 9:137,447,570-137,459,334 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Hypogonadotropic hypogonadism 9 with or without anosmia | 614838 | Autosomal dominant | 3 |
Kramer and Wray (2000) cloned mouse Nelf by differential screening of migrating (3.5 days in vitro) versus nonmigrating (10.5 days in vitro) primary luteinizing hormone-releasing hormone (LHRH; 152760) neurons. Nelf was expressed in peripheral and central nervous system tissues during embryonic development, including olfactory sensory cells and LHRH cells.
Using RT-PCR on a fetal brain cDNA library, Miura et al. (2004) detected 5 alternatively spliced variants of NELF. One of the variants, NELF-v1, has 93 to 94% identity at the amino acid level to mouse and rat Nelf, and 4 other transcripts are also highly conserved among human, rat, and mouse. A 3.0-kb transcript is expressed most highly in the adult and fetal brain, testis, and kidney, indicating that NELF plays a role in the function of these tissues.
Kramer and Wray (2000) presented evidence that mouse Nelf is a guidance molecule for olfactory axon projections and plays a role in the neurophilic migration of LHRH cells.
Miura et al. (2004) determined that the NELF gene contains 16 exons with a 1,590-bp open reading frame encoding 530 amino acids.
Miura et al. (2004) stated that the NELF gene maps to chromosome 9q34.3.
Because the mouse Nelf gene encodes a guidance molecule for the migration of the olfactory axon and gonadotropin-releasing hormone neurons, its human homolog is a candidate gene for hypogonadotropic hypogonadism and Kallmann syndrome (see HH9, 614838). Miura et al. (2004) reported studies of NELF, including mutation analysis, in 65 patients with hypogonadotropic hypogonadism. In one of the patients, they identified a thr480-to-ala mutation in the NELF gene (608137.0001). The mutation was not found in 100 normal control individuals.
In a family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome (see 126800), his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, Pitteloud et al. (2007) identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his sister. Heterozygosity for an additional mutation, an 8-bp intronic deletion in the NELF gene (608137.0002), was identified in the proband, his mother, and his brother. Pitteloud et al. (2007) concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in his unaffected brother, Tornberg et al. (2011) identified heterozygosity for a missense mutation in the HS6ST1 gene (604846.0001). Because of the reduced penetrance displayed in the family and phenotypic variability seen among other HH patients carrying the same HS6ST1 mutation, the authors analyzed 8 additional known HH-associated genes and detected a missense mutation in NELF that was present only in the affected brother (608137.0001). Tornberg et al. (2011) concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction.
In a sporadic case of hypogonadotropic hypogonadism (HH9; 614838), Miura et al. (2004) identified a heterozygous 1438A-G transition at the donor splice site in exon 15 of the NELF gene, resulting in a thr480-to-ala (T480A) mutation. This amino acid substitution switches from a polar side chain in threonine to a nonpolar side chain in alanine. As the mutation was not found in any of 100 control individuals, and thr480 is highly conserved among mouse, rat, and human, Miura et al. (2004) suggested that T480A was associated with the pathogenesis of hypogonadotropic hypogonadism in this case.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in his unaffected brother, Tornberg et al. (2011) identified heterozygosity for a missense mutation in the HS6ST1 gene (604846.0001). Because of the reduced penetrance displayed in the family and phenotypic variability seen among other HH patients carrying the same HS6ST1 mutation, the authors analyzed 8 additional known HH-associated genes and detected the T480A mutation in NELF in the affected brother but not in his unaffected sib.
In a family in which the proband had severe Kallmann syndrome (614838), his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, Pitteloud et al. (2007) identified heterozygosity for an intronic 8-bp deletion ending 14 bp before exon 10 (1159-14_-22del), resulting in a splicing defect of exon 10 and causing a premature stop codon, in the proband, his mother, and his brother. The deletion was not found in 384 controls. Heterozygosity for an additional missense mutation in the FGFR1 gene (L342S; 136350.0017) was identified in the proband, his father, and his sister. Pitteloud et al. (2007) concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency.
Kramer, P. R., Wray, S. Novel gene expressed in nasal region influences outgrowth of olfactory axons and migration of luteinizing hormone-releasing hormone (LHRH) neurons. Genes Dev. 14: 1824-1834, 2000. [PubMed: 10898796]
Miura, K., Acierno, J. S., Jr., Seminara, S. B. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J. Hum. Genet. 49: 265-268, 2004. [PubMed: 15362570] [Full Text: https://doi.org/10.1007/s10038-004-0137-4]
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117: 457-463, 2007. [PubMed: 17235395] [Full Text: https://doi.org/10.1172/JCI29884]
Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad. Sci. 108: 11524-11529, 2011. [PubMed: 21700882] [Full Text: https://doi.org/10.1073/pnas.1102284108]