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NUCLEAR FACTOR I/B; NFIB

NUCLEAR FACTOR I/B; NFIB

Alternative titles; symbolsTRANSCRIPTION FACTOR NFIBHGNC Approved Gene Symbol: NFIBCytogenetic location: 9p23-p22.3 Genomic coordinates (GRCh38): 9:14,081,84...

Alternative titles; symbols

  • TRANSCRIPTION FACTOR NFIB

HGNC Approved Gene Symbol: NFIB

Cytogenetic location: 9p23-p22.3 Genomic coordinates (GRCh38): 9:14,081,842-14,532,076 (from NCBI)

▼ Cloning and Expression
Liu et al. (1997) cloned and characterized 3 splice variants of NFIB. NFIB1 and NFIB2 are translated from an 8.7-kb message that encodes proteins containing an N-terminal DNA-binding domain and a C-terminal transactivation domain. NFIB3 is a truncated 188-amino acid protein, translated from a 1.8-kb message, that contains only the N-terminal DNA-binding domain. Northern blot analysis detected the 1.8-kb NFIB3 message in HeLa cells and fibroblasts, as well as in several human tissue samples. Using a different probe, Liu et al. (1997) detected an 8.7-kb species expressed in HeLa cells and different tissues, but not in fibroblasts.

By ortholog comparisons using protein sequences from 7 vertebrate species, Grunder et al. (2003) identified 8 NFIB variants that are produced by alternative splicing. Of these, 3 human NFIB splice variants, called NFIB2, NFIB2.1, and NFIB3, have coding regions of 1,261, 505, and 565 nucleotides, respectively. Only NFIB2 was predicted to encode a protein with both an N-terminal DNA-binding domain and nuclear localization signal. Translation of NFIB2.1 was predicted to initiate with a met codon in exon 5, and the deduced protein was predicted to lack a DNA-binding domain. NFIB3 encodes a protein truncated immediately after the DNA-binding domain.

▼ Gene Structure
Grunder et al. (2003) determined that the NFIB gene contains 12 exons.

▼ Mapping
Qian et al. (1995) mapped the NFIB gene to chromosome 9p24.1 by fluorescence in situ hybridization. By FISH, Grunder et al. (2003) mapped the mouse Nfib and Nfia genes to chromosome 4C4-C6.

▼ Gene Function
By expression in insect cells that do not contain NFI genes, Liu et al. (1997) found that the NFIB3 truncated isoform did not bind DNA and had no effect on the transcription of a reporter gene. Coexpression of NFIB3 with active isoforms of NFIB, NFIC (600729), and NFIX (164005), however, led to a strong repression of transcription by the other NFI proteins. Gel shift analysis indicated that NFIB3 formed heterodimers with the other NFI proteins and reduced their ability to bind DNA.

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.

Chang et al. (2013) identified transcription factor NFIB as an unanticipated coordinator of stem cell behavior in the hair follicle. Hair follicle stem cell-specific conditional targeting of Nfib in mice uncouples stem cell synchrony. Remarkably, this happens not by perturbing hair cycle and follicle architecture, but rather by promoting melanocyte stem cell proliferation and differentiation. The early production of melanin is restricted to melanocyte stem cells at the niche base. Melanocyte stem cells more distant from the dermal papilla are unscathed, thereby preventing hair graying typical of melanocyte stem cell differentiation mutants. Furthermore, Chang et al. (2013) pinpointed KIT ligand (184745) as a dermal papilla signal promoting melanocyte stem cell differentiation. Additionally, through chromatin immunoprecipitation with high-throughput sequencing and transcriptional profiling, Chang et al. (2013) identified endothelin-2 (EDN2; 131241) as an NFIB target aberrantly activated in NFIB-deficient hair follicle stem cells. Ectopically induced Edn2 recapitulated Nfib-deficiency phenotypes in wildtype mice. Conversely, endothelin receptor (see 131244) antagonists and/or Kit blocking antibodies prevented precocious melanocyte stem cell differentiation in the Nfib-deficient niche. Chang et al. (2013) concluded that their findings revealed how melanocytes and hair follicle stem cell behaviors maintain reliance upon cooperative factors within the niche, and how this can be uncoupled in injury, stress, and disease states.

▼ Cytogenetics
Approximately 12% of all pleomorphic adenomas of the salivary glands are characterized by chromosome aberrations involving 12q13-q15. Several chromosomes have been found as translocation partners of chromosome 12, and some of these are recurrent. The target gene on 12q13-q15 involved in the translocation is HMGIC (600698). Fusion partner genes include LPP (600700) on 3q, ALDH2 (100650) on 12q24.1, and FHIT (601153) on 3p. Using 3-prime-RACE analysis of a primary adenoma with an apparently normal karyotype, Geurts et al. (1998) found an HMGIC fusion transcript containing ectopic sequences derived from the NFIB gene. In a second adenoma with an ins(9;12)(p23;q12q15) as the sole anomaly, they also found an HMGIC/NFIB hybrid transcript. Nucleotide sequence analysis of the fusion transcripts indicated that the genetic aberration in both tumors resulted in the replacement of a carboxy-terminal segment of HMGIC by the last 5 amino acids of NFIB.

▼ Molecular Genetics
Schanze et al. (2018) reported 18 patients with acquired macrocephaly and impaired intellectual development (MACID; 618286). Eleven patients had deletions ranging from 225 kb to 4.2 Mb on chromosome 9p23-p22, with the smallest including only the NFIB gene. Eight patients from 7 families had NFIB mutations, including 3 nonsense, 1 frameshift, and 3 missense (609728.0001-609728.0007). Schanze et al. (2018) demonstrated that the missense mutations caused loss of function in luciferase assays. Schanze et al. (2018) concluded that MACID is caused by haploinsufficiency for NFIB.

▼ Animal Model
Grunder et al. (2002) noted that Nfib is highly expressed in embryonic mouse lung. They found that Nfib-null mice died early postnatally and displayed severe lung hypoplasia. Heterozygotes survived but exhibited delayed pulmonary differentiation. Mutant lungs failed to repress Tgfb (190180) and Shh (600725) expression during embryonic lung development. Grunder et al. (2002) concluded that NFIB is necessary for normal lung development and function.

Steele-Perkins et al. (2005) showed that Nfib is essential for both lung maturation and brain development. Piper et al. (2009) demonstrated that multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice. These knockout mouse embryos exhibited agenesis of the corpus callosum, enlarged ventricles, and hippocampal anomalies. Schanze et al. (2018) commented that Nfib knockout mouse embryos show increased progenitor cells associated with perturbed dorsal telencephalon; however, the effect on head size was unknown due to defects of lung development causing perinatal lethality. Schanze et al. (2018) developed a conditional knockout mouse model with Nfib deletion restricted to the telencephalon. Cre-treated mice had a longer and wider cortex and a 10% increase in brain volume. No significant structural changes were noted.

▼ ALLELIC VARIANTS ( 7 Selected Examples):

.0001 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, ARG37TER (SCV000803743.1)
In a 16-year-old boy (P1) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.109C-T transition (c.109C-T, NM_001190737.1) in exon 2 of the NFIB gene, resulting in a premature termination codon (R37X) at a highly conserved residue in the DNA binding and dimerization domain. The mutation was shown to have occurred as a de novo event. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

.0002 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, ARG89Ter (SCV000803744.1)
In a 7-year-old boy (P2) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.265C-T transition (c.265C-T, NM_001190737.1) in exon 2 of the NFIB gene, resulting in arg89-to-ter (R89X) substitution. DNA from the father was not available for testing. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

.0003 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, 2-BP DUP, 758TG (SCV000803748.1)
In a 33-year-old woman (P6a) with acquired macrocephaly and impaired intellectual development (MACID; 618286) and her similarly affected son (P6b), Schanze et al. (2018) identified heterozygosity for a 1-bp duplication (c.758_759dupTG, NM_001190737.1), resulting in a premature termination codon (R254X). The mutation was shown to have occurred as a de novo event in the mother. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

.0004 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, 14-BP DEL, NT1063 (SCV000803749.1)
In a 3-year-old girl (P7) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a 14-bp deletion (c.1063_1076del, NM_001190737.1) in exon 8 of the NFIB gene, resulting in a frameshift and premature termination (Ile355SerfsTer48). The mutation was shown to have occurred as a de novo event. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

.0005 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, LYS114THR (SCV000803745.1)
In an 8-year-old boy (P3) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.341A-C transversion (c.341A-C, NM_001190737.1) in exon 2 of the NFIB gene, resulting in a lys114-to-thr (K114T) substitution in the DNA binding and dimerization domain. DNA from the father was not available for testing. Luciferase assays showed that the mutation caused a loss of function. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

.0006 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, LYS126GLU (SCV000803746.1)
In a 32-year-old man (P4) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.376A-G transition (c.376A-G, NM_001190737.1) in exon 2 of the NFIB gene, resulting in a lys126-to-glu (K126E) substitution in the DNA binding and dimerization domain. The mutation was shown to have occurred as a de novo event. Luciferase assays showed that the mutation caused a loss of function. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

.0007 MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
NFIB, LEU132PRO (SCV000803747.1)
In a 7-year-old boy (P5) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.395T-C transition (c.395T-C, NM_001190737.1) in exon 2 of the NFIB gene, resulting in a leu132-to-pro (L312P) substitution in the DNA binding and dimerization domain. The mutation was shown to have occurred as a de novo event. Luciferase assays showed that the mutation caused a loss of function. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases.

Tags: 9p23, 9p22.3