Alternative titles; symbols
HGNC Approved Gene Symbol: FEZF1
Cytogenetic location: 7q31.32 Genomic coordinates (GRCh38) : 7:122,301,303-122,310,723 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.32 | Hypogonadotropic hypogonadism 22, with or without anosmia | 616030 | Autosomal recessive | 3 |
FEZF1 is a zinc-finger gene encoding a transcriptional repressor that is highly and selectively present during embryogenesis in the olfactory epithelium, amygdala, and hypothalamus (summary by Kotan et al., 2014).
Song et al. (2009) stated that the 475-amino acid human FEZF1 protein, which they called ZNF312B, contains 6 C2H2-type zinc finger domains in its C-terminal half and a proline-rich motif near its C terminus. It shares 55% amino acid identity with ZNF312 (FEZF2; 607414). Using immunohistochemical analysis, Song et al. (2009) found that ZNF312B showed nuclear expression in a transfected human gastric cancer cell line.
Hartz (2010) mapped the FEZF1 gene to chromosome 7q31.32 based on an alignment of the FEZF1 sequence (GenBank AY726588) with the genomic sequence (GRCh37).
Song et al. (2009) found that ZNF312B was overexpressed in human gastric cancer tissues and cell lines. Overexpression of ZNF312B induced accelerated proliferation in cultured cells and increased tumor mass in nude mice. ZNF312B translocated to the nucleus via its C-terminal proline-rich domain, and nuclear ZNF312B induced KRAS (190070) overexpression, resulting in activation of ERK (see 601795) signaling.
In 2 unrelated consanguineous Kurdish families with hypogonadotropic hypogonadism with anosmia (HH22; 616030), Kotan et al. (2014) identified homozygosity for a missense mutation (H278Y; 613301.0001) and a 1-bp deletion (c.651delT; 613301.0002), respectively, in the FEZF1 gene.
Hirata et al. (2006) stated that Fezf1 and Fezf2, which they called Fez and Fezl, respectively, are transcriptional repressors that are expressed in overlapping domains in the forebrain during mouse and zebrafish development. Fezl is required for development of subcerebral projection neurons in layer V of the neocortex, and Fezl-deficient mice show abnormal formation of subplate neurons and thalamocortical axons and loss of the fornix/fimbria system. Using mice deficient in both Fez and Fezl, Hirata et al. (2006) showed that these transcription factors redundantly controlled rostrocaudal patterning of the diencephalon by repressing the caudal diencephalon fate in the prospective prethalamic region. Fez and Fezl were also required for formation of the zona limitans intrathalamica at the boundary between the prethalamus and thalamus.
In a sister and brother from a consanguineous Kurdish family with hypogonadotropic hypogonadism with anosmia (HH22; 616030), Kotan et al. (2014) identified homozygosity for a c.832C-T transition in the FEZF1 gene, resulting in a his278-to-tyr (H278Y) substitution at a highly conserved residue within the C(2)H(2) motif, which is required for the stability of the central zinc in zinc finger proteins. The patients' unaffected parents and 3 unaffected sibs were each heterozygous for the mutation, which was not found in 100 ethnically matched controls, 36 in-house whole exomes, or the dbSNP (build 136), 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. By immunoblot analysis of transfected HEK293T cells, Kotan et al. (2014) observed that wildtype FEZF1 reduced accumulation of the HES5 (607348)-DsRed reporter, whereas the H278Y mutant accumulated intermediate levels of DsRed, indicating a partial loss of function. Kotan et al. (2014) noted that both affected individuals were also homozygous for a nonsense mutation in the CCDC141 gene (616031), for which all unaffected family members were heterozygous.
In 2 brothers from a consanguineous Kurdish family with hypogonadotropic hypogonadism-22 with anosmia (HH22; 616030), Kotan et al. (2014) identified homozygosity for a 1-bp deletion (c.651delT) in the FEZF1 gene, causing a frameshift predicted to result in a premature termination codon (Ala217fsTer13). The patients' unaffected parents and 3 unaffected sibs were each heterozygous for the mutation, which was not found in 100 ethnically matched controls, 36 in-house whole exomes, or the dbSNP (build 136), 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. (In the article by Kotan et al. (2014), the nucleotide deletion is given as c.651delT and as c.652del. Topaloglu (2014) indicated that c.651delT is correct.)
Hartz, P. A. Personal Communication. Baltimore, Md. 3/12/2010.
Hirata, T., Nakazawa, M., Muraoka, O., Nakayama, R., Suda, Y., Hibi, M. Zinc-finger genes Fez and Fez-like function in the establishment of diencephalon subdivisions. Development 133: 3993-4004, 2006. [PubMed: 16971467] [Full Text: https://doi.org/10.1242/dev.02585]
Kotan, L. D., Hutchins, B. I., Ozkan, Y., Demirel, F., Stoner, H., Cheng, P. J., Esen, I., Gurbuz, F., Bicakci, Y. K., Mengen, E., Yuksel, B., Wray, S., Topaloglu, A. K. Mutations in FEZF1 cause Kallmann syndrome. Am. J. Hum. Genet. 95: 326-331, 2014. [PubMed: 25192046] [Full Text: https://doi.org/10.1016/j.ajhg.2014.08.006]
Song, I.-S., Oh, N. S., Kim, H.-T., Ha, G.-H., Jeong, S.-Y., Kim, J.-M., Kim, D.-I., Yoo, H.-S., Kim, C.-H., Kim, N.-S. Human ZNF312b promotes the progression of gastric cancer by transcriptional activation of the K-ras gene. Cancer Res. 69: 3131-3139, 2009. Note: Erratum: Cancer Res. 69: 4092 only, 2009. [PubMed: 19318583] [Full Text: https://doi.org/10.1158/0008-5472.CAN-08-2240]
Topaloglu, A. K. Personal Communication. Adana, Turkey 9/23/2014.