Alternative titles; symbols
HGNC Approved Gene Symbol: NFIX
SNOMEDCT: 73284007, 763795006;
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38) : 19:12,995,475-13,098,796 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.13 | Malan syndrome | 614753 | Autosomal dominant | 3 |
| Marshall-Smith syndrome | 602535 | Autosomal dominant | 3 |
NFIX belongs to a family of CCAAT-binding transcription factors that can initiate transcription of both vertebrate and viral genes (Santoro et al., 1988).
Nuclear factor I is a ubiquitous 47-kD dimeric DNA-binding protein whose recognition sequence, TGG(C/A)N(5)GCCAA, is found in the genomes of a number of DNA viruses. The same sequence occurs frequently in the human genome. The NFI protein stimulates initiation of adenovirus DNA replication in vitro and is capable of stimulating the transcription of genes in cooperation with other factors, such as the estrogen receptor (ESR; 133430). Santoro et al. (1988) gave a detailed analysis of NFI cDNAs isolated from the human, which, with similar analyses in other species, indicated that it is a member of a family of related proteins. Four known variants were referred to as CTF, X, L, and Red. These are the products of different genes, some of which (e.g., the first, CTF, later symbolized NFIC; 600729) are subject to differential splicing.
Seisenberger et al. (1993) isolated 2 phages containing the second exon and flanking intron regions of the human gene for NFI/X, which has been designated NFIX.
Qian et al. (1995) isolated partial cDNA sequences from 4 nuclear factor I proteins: NFIA (600727), NFIB (600728), NFIC, and NFIX.
Grunder et al. (2003) identified 5 human NFIX splice variants have coding regions of 1,324, 1,300, 1,270, 469, and 433 nucleotides. The 2 longest protein isoforms have 4 conserved cysteines in an N-terminal DNA-binding domain, followed by a nuclear localization signal. Other NFIX isoforms lack the nuclear localization signal or part or all of the DNA-binding domain.
Malan et al. (2010) performed RT-PCR analysis and demonstrated ubiquitous expression of NFIX in all human tissues and cell types tested, including chondrocytes and osteoblasts. In situ hybridization in normal human embryos at CS17 (gestational day 42) showed a nearly ubiquitous expression of NFIX, with prominent expression in the central nervous system and the peripheral nervous system. In fetal brain at 22 weeks' gestation, NFIX was expressed in the cerebral cortex, in the hippocampus, and faintly in the thalamus. In the skeleton, NFIX expression was first noticed at CS17 in the mandibular arch, the cartilage primordium of the humerus, the scapula, and the vertebrae. In the limb, NFIX expression was first observed at CS17 in the perichondrium. At 14 weeks' gestation, NFIX was highly expressed in the proliferating zone of the digit. The study of distal femoral growth plates of 1- to 5-week-old mice and human fetus revealed strong NFIX expression in bone and in prehypertrophic chondrocytes.
Grunder et al. (2003) determined that the NFIX gene contains 11 exons. By ortholog comparisons using protein sequences from 7 vertebrate species, they identified 9 NFIX variants that are produced by alternative splicing.
By fluorescence in situ hybridization, Seisenberger et al. (1993) mapped the NFIX gene to 19p13. Secondary sites of hybridization were observed at 5p15, 1q42-q44, 1p22-p21, and 20p1.3; this hybridization was attributed to partial sequence homologies with related NFI genes.
By FISH, Qian et al. (1995) mapped the NFIA and NFIB genes to chromosomes 1p31.3-p31.2 and 9p24.1, respectively. The NFIC and NFIX genes were both localized to 19p13.3 in the order cen--NFIX--NFIC--tel. Comparison of the position of NFI genes and JUN genes revealed a close physical linkage between members of the NFI and JUN gene families; for example, one JUN gene (165160) is on 1p32-p31, and both JUNB (165161) and JUND (165162) are located on 19p.
Scherthan et al. (1994) used fluorescence in situ hybridization to map the murine Nfix gene to chromosome 8C1-C2, confirming the segmental homology between human chromosome 19p13 and mouse chromosome 8C. Although the location of the other NFI genes in the mouse had not been established, Qian et al. (1995) suggested that from the imperative map between human and mouse, the Nfia could be predicted to be located on mouse chromosome 4 where the murine c-jun is located and the Nfic locus on mouse chromosome 8 where the murine junD and junB genes are located. They speculated further that a genomic unit containing an ancestral NFI gene and an ancestral JUN gene existed early in evolution, later duplicated twice, and then underwent further changes. If this hypothesis is correct, one can suspect the existence of a fourth member of the JUN gene family, probably located close to the NFIB gene. The postulated fourth JUN gene would then be predicted to map to human 9 at 9p24.1 and murine chromosome 4.
By FISH, Grunder et al. (2003) mapped the mouse Nfix gene to the distal region of chromosome 8C.
Malan Syndrome
Malan et al. (2010) used a high-resolution array CGH in 18 patients with unexplained syndromic overgrowth and identified 2 patients with a de novo 19p13.1 monosomy. The deletions involved a single common gene, NFIX. Malan et al. (2010) then screened 76 patients with unexplained syndromic overgrowth for NIFX mutations and identified a heterozygous nonsense mutation (Q190X; 164005.0001) in 1 patient with Malan syndrome (MALNS; 614753), who had been diagnosed with a 'Sotos-like syndrome' (see SOTOS, 117550). This patient and the 2 patients with 19p13.1 monosomy had a similar phenotype consisting of postnatal overgrowth, macrocephaly, advanced bone age, long narrow face, high forehead, slender habitus, scoliosis, unusual behavior characterized especially by anxiety, and mental retardation. The variant was not observed in 300 control chromosomes.
Yoneda et al. (2012) examined NFIX by high-resolution melt analysis in 48 individuals who were suspected of having Sotos syndrome but who did not have NSD1 (606681) abnormalities, which are found in Sotos syndrome. They identified 2 heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein (164005.0011-164005.0012). Neither mutation was found in 250 healthy Japanese controls.
Marshall-Smith Syndrome
Based on an Nfix-deficient mouse model with a phenotype similar to that in Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) screened 9 individuals with MRSHSS for NFIX mutations and found heterozygosity for 7 independent frameshift mutations (164005.0002-164005.0008) and 2 different mutations within the donor splice site of exon 6 (164005.0009-164005.0010). All of the mutations occurred de novo and were not found in 300 control chromosomes.
Schanze et al. (2014) analyzed the NFIX gene in 17 patients with a clinical diagnosis of MRSHSS and identified heterozygous mutations in all, confirming that MRSHSS is a genetically homogeneous mendelian disorder. Frameshift or splicing mutations were present in 10 patients (see, e.g., 164005.0013), 5 patients carried almost-identical deletions of exons 6 and 7 (see, e.g., 164005.0014), and 2 patients had smaller deletions involving exon 6 (see, e.g., 164005.0015). The authors noted that predicted MRSHSS-associated mutant NFIX proteins all have a preserved DNA binding and dimerization domain, whereas they vary widely in their C-terminal portion, supporting the hypothesis that MRSHSS-associated mutations encode dysfunctional proteins that act in a dominant-negative manner. The patients exhibited a consistent phenotype, with no obvious correlation between phenotype and specific alterations of the C-terminal portion of the NFIX protein.
Malan et al. (2010) performed RT-PCR analysis of skin fibroblasts in 1 MALNS patient and 3 MRSHSS patients with NFIX mutations. They showed that the MALNS phenotype is due to NFIX haploinsufficiency, whereas the mutated RNAs in MRSHSS escape nonsense-mediated decay surveillance. Malan et al. (2010) suggested that NFIX mutations causing MRSHSS generate mutant proteins able to exert a dominant-negative effect over the wildtype allele and result in a more severe phenotype closely resembling the knockout mouse model phenotype.
Martinez et al. (2015) reported 5 de novo mutations in the NFIX gene, including 1 splicing and 2 frameshift mutations in 3 patients with MRSHSS, and 2 missense mutations in the DNA-binding/dimerization domain in 2 patients with Malan syndrome. The authors reviewed previously reported NFIX mutations and concluded that MRSHSS-associated mutations are scattered through exons 6 to 10 of the gene, whereas most point mutations causing MALNS are clustered in exon 2.
Driller et al. (2007) obtained Nfix -/- mice at a normal mendelian ratio, but nearly all died before 1 month of age. Although Nfix -/- newborns appeared normal, they developed a dome-shaped head, were unable to fully open their eyes, had deformation of the spine, exhibited an ataxic gait, and were unable to gain weight. Heterozygous mice showed a slight weight reduction, but had no obvious anatomic or behavioral defects. Except for reduced size, most organs of Nfix -/- mice appeared histologically normal. However, the smaller digestive tract showed pathologic thinning of intestinal walls and reduced blood supply, and a general loss of muscle tissue was observed. Hydrocephalus, which developed after birth and progressed with age, was associated with partial agenesis of the corpus callosum in Nfix -/- and Nfix +/- mice. Skeletal pathology, including impaired endochondral ossification and decreased mineralization in femoral bone, also progressed with age and was associated with reduced expression of tetranecin (TNA; 187520), a protein involved in mineralization.
Campbell et al. (2008) found that the majority of Nfix -/- mice died before 1 month of age. However, those that survived to adulthood were fertile. Nfix -/- neonates showed a variety of brain abnormalities and delay in eye and ear opening.
Studies using mouse models found that Nfix is involved in hippocampal-dependent behavior (Harris et al., 2013), early B lymphopoiesis and myelopoiesis (O'Connor et al., 2015), neural stem/progenitor cell fate (Zhou et al., 2015), and cell proliferation, migration, and gene expression in the subventricular zone (Heng et al., 2015).
In a patient with Malan syndrome (MALNS; 614753), Malan et al. (2010) identified a heterozygous de novo 568C-T transition within exon 3 of the NFIX gene, predicting a gln190-to-ter (Q190X) substitution. RT-PCR analysis of NFIX RNA in skin fibroblasts from this patient showed the expression of a single wildtype allele, indicating nonsense-mediated mRNA decay and haploinsufficiency.
In a 2-year-old patient from India with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 2-bp deletion in the NFIX gene (1011_1012delTC), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 3-year-old patient from the Netherlands with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 1-bp insertion in the NFIX gene (1037_1038insT), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 6-year-old patient from Brazil with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 5-bp deletion in the NFIX gene (1008_1012delCTCTC), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 7-year-old patient from Portugal with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 1-bp insertion in the NFIX gene (1048_1049insC), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 7-year-old French patient with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 1-bp deletion in the NFIX gene (1243delG), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 16-year-old British patient with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 1-bp insertion in the NFIX gene (994_995insT), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 21-year-old British patient with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous 1-bp insertion in the NFIX gene (959_960insC), resulting in a frameshift and premature termination. The mutation occurred de novo and was not observed in 300 control chromosomes.
In a 3-week-old patient with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous splice site mutation (955+1G-A). The mutation occurred de novo and was not observed in 300 control chromosomes. Both normal and mutated alleles were found in patient fibroblasts, suggesting that the mutation escapes nonsense-mediated decay and has a dominant-negative effect.
In a 6-month-old patient from Croatia with Marshall-Smith syndrome (MRSHSS; 602535), Malan et al. (2010) identified a heterozygous splice site mutation in the NFIX gene (955+1G-T). The mutation occurred de novo and was not observed in 300 control chromosomes.
In a female infant (patient 3) with MRSHSS, who died at 17 days of life due to respiratory failure, Martinez et al. (2015) identified heterozygosity for the IVS6+1G-T transversion (c.955+1G-T, NM_001271043.1) in the NFIX gene. The variant was shown to have arisen de novo.
In a 17-year-old female with Malan syndrome (MALNS; 614753), Yoneda et al. (2012) identified a heterozygous 179T-C transition in the NFIX gene, resulting in a leu60-to-pro (L60P) substitution in the DNA-binding/dimerization domain. The mutation occurred de novo and was not found in 250 healthy Japanese controls.
In a 14-year-old male with Malan syndrome (MALNS; 614753), Yoneda et al. (2012) identified a heterozygous 362G-C transversion in the NFIX gene, resulting in an arg121-to-pro (R121P) substitution in the DNA-binding/dimerization domain. The mutation may have been inherited from his mother who was not available for study. The mutation was not found in 250 healthy Japanese controls.
In 2 unrelated male patients (P6 and P12) with Marshall-Smith syndrome (MRSHSS; 602535), Schanze et al. (2014) identified heterozygosity for a 1-bp deletion (c.1456delC, ENST00000592199) in exon 10 of the NFIX gene, causing a frameshift predicted to result in a premature termination codon (Arg486GlyfsTer6). The mutation occurred de novo in both probands.
In a female patient (P14) with Marshall-Smith syndrome (MRSHSS; 602535) who was originally described by Adam et al. (2005) (patient 3), Schanze et al. (2014) identified heterozygosity for a de novo 5.9-kb deletion (c.819-484_1079-700del, ENST00000592199), involving loss of exons 6 and 7 of the NFIX gene and causing a frameshift predicted to result in a premature termination codon (Ser273ArgfsTer63). Sequence analysis revealed that the distal and proximal breakpoints are located within 2 AluY repeats in intron 5 and intron 7, respectively; these elements have 92% sequence identity and are oriented in parallel. Genotyping the proband and her parents for 2 common SNPs located within the deleted region showed that the deletion arose on the paternal allele. The authors identified almost identical deletions involving NFIX exons 6 and 7 in 4 more patients with MRSHSS, and stated that this was the first recurrent mutation reported in MRSHSS patients.
In a male patient (P13) with Marshall-Smith syndrome (MRSHSS; 602535) who was originally described by Dernedde et al. (1998), Schanze et al. (2014) identified heterozygosity for a deletion of exon 6 (c.818+561_956-804del, ENST00000592199) of the NFIX gene, causing a frameshift predicted to result in a premature termination codon (Ser273ArgfsTer104). The deletion spanned 3,223 bp, comprising all of exon 6, with breakpoints in introns 5 and 6 that did not involve AluY elements. DNA was unavailable from the parents for segregation analysis.
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Martinez, F., Marin-Reina, P., Sanchis-Calvo, A., Perez-Aytes, A., Oltra, S., Rosello, M., Mayo, S., Monfort, S., Pantoja, J., Orellana, C. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes. Pediat. Res. 78: 533-539, 2015. [PubMed: 26200704] [Full Text: https://doi.org/10.1038/pr.2015.135]
O'Connor, C., Campos, J., Osinski, J. M., Gronostajski, R. M., Michie, A. M., Keeshan, K. Nfix expression critically modulates early B lymphopoiesis and myelopoiesis. PLoS One 10: e0120102, 2015. Note: Electronic Article. [PubMed: 25780920] [Full Text: https://doi.org/10.1371/journal.pone.0120102]
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Zhou, B., Osinski, J. M., Mateo, J. L., Martynoga, B., Sim, F. J., Campbell, C. E., Guillemot, F., Piper, M., Gronostajski, R. M. Loss of NFIX transcription factor biases postnatal neural stem/progenitor cells toward oligodendrogenesis. Stem Cells Dev. 24: 2114-2126, 2015. [PubMed: 26083238] [Full Text: https://doi.org/10.1089/scd.2015.0136]