Alternative titles; symbols
HGNC Approved Gene Symbol: NHLH2
Cytogenetic location: 1p13.1 Genomic coordinates (GRCh38): 1:115,831,344-115,841,126 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.1 | ?Hypogonadotropic hypogonadism 27 without anosmia | 619755 | Autosomal recessive | 3 |
Brown et al. (1992) identified 2 structurally similar genes, denoted HEN1 (NHLH1; 162360) and HEN2 (NHLH2), the gene products of which are regulatory molecules that possess the DNA-binding and dimerization motif known as the basic helix-loop-helix (bHLH) domain. HEN1 and HEN2 are coexpressed in a human neuroblastoma cell line.
By fluorescence in situ hybridization, Lipkowitz et al. (1992) mapped the NHLH2 gene to chromosome 1p12-p11.
Li et al. (2001) found that expression of NSCL2 in the chick is restricted to amacrine and horizontal cells. Retroviral-driven misexpression of NSCL2 caused Muller glial atrophy followed by photoreceptor degeneration.
Using yeast 2-hybrid analysis, protein pull-down assays, and coimmunoprecipitation assays, Han et al. (2005) found that human LMO2 (180385) interacted with human BEX2 (300691). Electrophoretic mobility shift assays showed that BEX2 and LMO2 were part of a DNA-binding complex that recognized the E-box element. Other components of this complex included NSCL2 and LDB1 (603451). LMO2 directly bound NSCL2 and upregulated NSCL2-dependent transcriptional activity, and BEX2 augmented this effect.
By exome screening in a cohort of 354 Turkish patients with hypogonadotropic hypogonadism (HH27; 619755), Topaloglu et al. (2022) identified a 19-year-old man (patient 1) with HH and obesity who was homozygous for a missense mutation in the NHLH2 gene (R79C; 162361.0001). His unaffected consanguineous parents and unaffected sister were heterozygous for the mutation, which was not found in Turkish controls or public variant databases. Functional analysis demonstrated impaired binding of the mutant to the MC4R (155541) promoter as well as impaired transactivation of the KISS1 (603286) promoter.
During murine embryogenesis, Nhlh1 and Nhlh2 share an overlapping but distinct pattern of expression in the developing nervous system. To improve understanding of the role of these genes during neurogenesis, Good et al. (1997) generated mice containing targeted deletions of both genes. Loss of Nhlh2 resulted in disruption of the hypothalamic-pituitary axis. Male Nhlh2 -/- mice were microphallic, hypogonadal, and infertile with alterations in circulating gonadotropins, a defect in spermatogenesis, and a loss of instinctual male sexual behavior. Female Nhlh2 -/- mice reared alone were hypogonadal, but when reared in the presence of males, their ovaries and uteri developed normally and they were fertile. Both male and female homozygotes exhibited progressive adult-onset obesity. Nhlh2 is expressed in the ventral-medial and lateral hypothalamus, Rathke pouch, and the anterior lobe of the adult pituitary. The findings of Good et al. (1997) supported a role for Nhlh2 in the onset of puberty and the regulation of body weight.
In a 19-year-old Turkish man with hypogonadotropic hypogonadism without anosmia (HH27; 619755), who had onset of obesity in early adolescence, Topaloglu et al. (2022) identified homozygosity for a c.235C-T transition (c.235C-T, NM_001111061.1) in the NHLH2 gene, resulting in an arg79-to-cys (R79C) substitution at a highly conserved residue within the Myc-type basic helix-loop-helix DNA-binding domain. His unaffected consanguineous parents and an unaffected sister were heterozygous for the mutation, which was not found in 100 Turkish controls or in the gnomAD database. Chromatin immunoprecipitation of transfected mouse N29/2 hypothalamic cells demonstrated little to no binding to the MC4R (155541) promoter region with the R79C mutant compared to wildtype Nhlh2. Studies in transfected HEK293 cells revealed markedly reduced transactivation of the KISS1 (603286) promoter with the R79C mutant compared to wildtype NHLH2.
Brown, L., Espinosa, R., III, Le Beau, M. M., Siciliano, M. J., Baer, R. HEN1 and HEN2: a subgroup of basic helix-loop-helix genes that are coexpressed in a human neuroblastoma. Proc. Nat. Acad. Sci. 89: 8492-8496, 1992. [PubMed: 1528853] [Full Text: https://doi.org/10.1073/pnas.89.18.8492]
Good, D. J., Porter, F. D., Mahon, K. A., Parlow, A. F., Westphal, H., Kirsch, I. R. Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nature Genet. 15: 397-401, 1997. [PubMed: 9090387] [Full Text: https://doi.org/10.1038/ng0497-397]
Han, C., Liu, H., Liu, J., Yin, K., Xie, Y., Shen, X., Wang, Y., Yuan, J., Qiang, B., Liu, Y.-J., Peng, X. Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex. Nucleic Acids Res. 33: 6555-6565, 2005. [PubMed: 16314316] [Full Text: https://doi.org/10.1093/nar/gki964]
Li, C.-M., Yan, R.-T., Wang, S.-Z. Atrophy of Muller glia and photoreceptor cells in chick retina misexpressing cNSCL2. Invest. Ophthal. Vis. Sci. 42: 3103-3109, 2001. [PubMed: 11726609]
Lipkowitz, S., Gobel, V., Varterasian, M. L., Nakahara, K., Tchorz, K., Kirsch, I. R. A comparative structural characterization of the human NSCL-1 and NSCL-2 genes: two basic helix-loop-helix genes expressed in the developing nervous system. J. Biol. Chem. 267: 21065-21071, 1992. [PubMed: 1328219]
Topaloglu, A. K., Simsek, E., Kocher, M. A., Mammadova, J., Bober, E., Kotan, L. M., Turan, I., Celiloglu, C., Gurbuz, F., Yuksel, B., Good, D. J. Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans. Hum. Genet. 141: 295-304, 2022. [PubMed: 35066646] [Full Text: https://doi.org/10.1007/s00439-021-02422-9]