Alternative titles; symbols
HGNC Approved Gene Symbol: NFIA
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38) : 1:61,077,227-61,462,788 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p31.3 | Brain malformations with or without urinary tract defects | 613735 | Autosomal dominant | 3 |
Nuclear factor I (NFI) proteins, such as NFIA, constitute a family of dimeric DNA-binding proteins with similar, and possibly identical, DNA-binding specificity. They function as cellular transcription factors and as replication factors for adenovirus DNA replication. Diversity in this protein family is generated by multiple genes, differential splicing, and heterodimerization (summary by Qian et al., 1995).
Qian et al. (1995) isolated partial cDNA sequences derived from 4 independent genes: NFIA, NFIB (600728), NFIC (600729), and NFIX (164005).
By sequencing clones obtained from an adult brain cDNA library, Nagase et al. (2000) cloned NFIA, which they designated KIAA1439. The deduced protein contains 561 amino acids and shares complete sequence identity with rat nuclear factor-1 over 509 amino acids. RT-PCR ELISA detected moderate to high expression in all tissues examined. Highest expression was detected in heart and liver, followed by brain, lung, ovary, skeletal muscle, kidney, testis, fetal liver, fetal brain, pancreas, and spleen. NFIA was expressed at moderate to high levels in all adult brain regions tested, with highest expression in cerebellum and caudate nucleus.
By ortholog comparisons using protein sequences from 7 vertebrate species, Grunder et al. (2003) identified 12 NFIA variants that are produced by alternative splicing. All of the 5 human NFIA splice variants identified encode proteins with 4 conserved cysteines in an N-terminal DNA-binding domain, and all but 1 were predicted to have a nuclear localization signal.
Grunder et al. (2003) determined that the NFIA gene contains 11 exons.
By FISH, Qian et al. (1995) mapped the NFIA and NFIB genes to chromosomes 1p31.3-p31.2 and 9p24.1, respectively. They localized the NFIC and NFIX genes to chromosome 19p13.3 in the order cen--NFIX--NFIC--tel. Comparison of the position of NFI genes and JUN genes (see JUNB, 165161) revealed a close physical linkage between members of the NFI and JUN gene families in the human genome.
By FISH, Grunder et al. (2003) mapped the mouse Nfia and Nfib genes to chromosome 4C4-C6.
Deneen et al. (2006) found that Nfia and Nfib were induced in the spinal cord ventricular zone of mouse embryos concomitant with induction of Glast (SLC1A3; 600111), a marker of gliogenesis. Using mouse and chicken embryos and embryonic rat cortical progenitor cells, they showed that Nfia and Nfib were necessary and sufficient to promote glial cell fate specification. At later embryonic stages, Nfia and Nfib promoted terminal astrocyte differentiation. Nfia also inhibited neurogenesis in ventricular zone progenitors.
Rosa et al. (2007) identified a pathway by which PU.1 (SPI1; 165170) regulated human monocyte/macrophage differentiation. PU.1 activated transcription of MIR424 (300682), which translationally repressed NFIA, resulting in activation of differentiation-specific genes, such as MCSFR (CSF1R; 164770).
Lu et al. (2007) reported 5 patients, including 2 half sibs, with balanced translocations or interstitial deletions of chromosome 1q31-q32 (613735) involving the NFIA gene confirmed by FISH and Southern blot analysis. Three of the patients had been previously reported by Campbell et al. (2002) and Shanske et al. (2004). The 2 half sibs had a 12-Mb deletion involving approximately 47 additional genes, and another patient had a 12-Mb deletion of chromosome 2q encompassing 39 additional genes, as well as a translocation involving chromosome 1p. The remaining 2 patients had a translocation with a microdeletion and a translocation, respectively. All 5 showed a similar phenotype characterized by hypoplastic or absent corpus callosum, hydrocephalus or ventriculomegaly, and developmental delay. Four patients had a tethered spinal cord, 3 had Chiari type I malformation, and 3 had seizures. In addition, 3 patients had urinary tract defects, including vesicoureteral reflux and urinary incontinence. Although all 5 cases had haploinsufficiency of NFIA, each case also had involvement of 1 or more additional genes, which may have contributed to the phenotype. Intragenic mutations in the NFIA gene were not identified in any of the patients or in 219 additional patients with various neurologic developmental abnormalities. Lu et al. (2007) noted the phenotypic similarities to Nfia loss of function in the mouse and suggested that haploinsufficiency of the NFIA gene contributed to the malformation syndrome in these patients.
Brain Malformations with or without Urinary Tract Defects
In a girl with brain malformations and urinary tract defects (BRMUTD; 613735), Rao et al. (2014) identified a de novo heterozygous 120-kb intragenic deletion of the NFIA gene (600727.0001). The deletion was found by CGH microarray analysis. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a truncated protein and haploinsufficiency.
In a Japanese boy with brain malformations and urinary tract defects, Negishi et al. (2015) identified a de novo heterozygous frameshift mutation in the NFIA gene (600727.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a truncated protein and haploinsufficiency.
In 4 members of a family with BRMUTD, Nyboe et al. (2015) identified a heterozygous 109-kb intragenic deletion affecting exons 1 and 2 of the NFIA gene (600727.0003). The deletion in the proband was found by array CGH analysis and confirmed in her father and her 2 sibs by quantitative PCR. Functional studies were not performed.
Das Neves et al. (1999) found that disruption of the mouse Nfia gene caused perinatal lethality. More than 95% of Nfia null animals died within 2 weeks after birth. Newborn animals lacked a corpus callosum and showed ventricular dilation indicating early hydrocephalus. Rare surviving homozygous mice lacked a corpus callosum, showed severe communicating hydrocephalus, a full-axial tremor indicative of neurologic defects, male sterility, and low female fertility, but they had near normal life spans.
In a girl with brain malformations and urinary tract defects (BRMUTD; 613735), Rao et al. (2014) identified a de novo heterozygous 120-kb intragenic deletion of the NFIA gene, resulting in an in-frame deletion of exons 4 through 9. The deletion was found by CGH microarray analysis. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a truncated protein and haploinsufficiency.
In a Japanese boy with brain malformations and urinary tract defects (BRMUTD; 613735), Negishi et al. (2015) identified a de novo heterozygous 1-bp deletion (c.1094delC, NM_001134673.3) in the NFIA gene, resulting in a frameshift and premature termination (Pro365HisfsTer32). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases or in 154 Japanese controls. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a truncated protein and haploinsufficiency.
In 4 members of a family with brain malformations with or without urinary tract defects (BRMUTD; 613735), Nyboe et al. (2015) identified heterozygosity for a 109-kb intragenic deletion (chr1.61,497,698-61,607,171, GRCh37) that affected exons 1 and 2 of the NFIA gene. The deletion in the proband was found by array CGH analysis and confirmed in her father and her 2 sibs by quantitative PCR. Only the father and 1 sib had urinary tract defects. No functional studies were performed.
Campbell, C. G. N., Wang, H., Hunter, G. W. Interstitial microdeletion of chromosome 1p in two siblings. Am. J. Med. Genet. 111: 289-294, 2002. [PubMed: 12210325] [Full Text: https://doi.org/10.1002/ajmg.10595]
das Neves, L., Duchala, C. S., Godinho, F., Haxhiu, M. A., Colmenares, C., Macklin, W. B., Campbell, C. E., Butz, K. G., Gronostajski, R. M. Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc. Nat. Acad. Sci. 96: 11946-11951, 1999. Note: Erratum: Proc. Nat. Acad. Sci. 98: 4276 only, 2001. [PubMed: 10518556] [Full Text: https://doi.org/10.1073/pnas.96.21.11946]
Deneen, B., Ho, R., Lukaszewicz, A., Hochstim, C. J., Gronostajski, R. M., Anderson, D. J. The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52: 953-968, 2006. [PubMed: 17178400] [Full Text: https://doi.org/10.1016/j.neuron.2006.11.019]
Grunder, A., Qian, F., Ebel, T. T., Mincheva, A., Lichter, P., Kruse, U., Sippel, A. E. Genomic organization, splice products and mouse chromosomal localization of genes for transcription factor nuclear factor one. Gene 304: 171-181, 2003. [PubMed: 12568726] [Full Text: https://doi.org/10.1016/s0378-1119(02)01204-0]
Lu, W., Quintero-Rivera, F., Fan, Y., Alkuraya, F. S., Donovan, D. J., Xi, Q., Turbe-Doan, A., Li, Q.-G., Campbell, C. G., Shanske, A. L., Sherr, E. H., Ahmad, A., and 16 others. NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects. PLoS Genet. 3: e80, 2007. Note: Electronic Article. [PubMed: 17530927] [Full Text: https://doi.org/10.1371/journal.pgen.0030080]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Negishi, Y., Miya, F., Hattori, A., Mizuno, K., Hori, I., Ando, N., Okamoto, N. Kato, M., Tsunoda, T., Yamasaki, M., Kanemura, Y., Kosaki, K., Saitoh, S. Truncating mutation in NFIA causes brain malformation and urinary tract defects. Hum. Genome Var. 2: 15007, 2015. Note: Electronic Article. [PubMed: 27081522] [Full Text: https://doi.org/10.1038/hgv.2015.7]
Nyboe, D., Kreiborg, S., Kirchhoff, M., Hove, H. B. Familial craniosynostosis associated with a microdeletion involving the NFIA gene. Clin. Dysmorph. 24: 109-112, 2015. [PubMed: 25714559] [Full Text: https://doi.org/10.1097/MCD.0000000000000079]
Qian, F., Kruse, U., Lichter, P., Sippel, A. E. Chromosomal localization of the four genes (NFIA, B, C, and X) for the human transcription factor nuclear factor I by FISH. Genomics 28: 66-73, 1995. [PubMed: 7590749] [Full Text: https://doi.org/10.1006/geno.1995.1107]
Rao, A., O'Donnell, S., Bain, N., Meldrum, C., Shorter, D., Goel, H. An intragenic deletion of the NFIA gene in a patient with a hypoplastic corpus callosum, craniofacial abnormalities and urinary tract defects. Europ. J. Med. Genet. 57: 65-70, 2014. [PubMed: 24462883] [Full Text: https://doi.org/10.1016/j.ejmg.2013.12.011]
Rosa, A., Ballarino, M., Sorrentino, A., Sthandier, O., De Angelis, F. G., Marchioni, M., Masella, B., Guarini, A., Fatica, A., Peschle, C., Bozzoni, I. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc. Nat. Acad. Sci. 104: 19849-19854, 2007. [PubMed: 18056638] [Full Text: https://doi.org/10.1073/pnas.0706963104]
Shanske, A. L., Edelmann, L., Kardon, N. B., Gosset, P., Levy, B. Detection of an interstitial deletion of 2q21-22 by high resolution comparative genomic hybridization in a child with multiple congenital anomalies and an apparent balanced translocation. Am. J. Med. Genet. 131A: 29-35, 2004. [PubMed: 15368480] [Full Text: https://doi.org/10.1002/ajmg.a.30311]