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SMAD NUCLEAR INTERACTING PROTEIN 1; SNIP1

SMAD NUCLEAR INTERACTING PROTEIN 1; SNIP1

HGNC Approved Gene Symbol: SNIP1Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:37,534,448-37,554,292 (from NCBI)▼ DescriptionThe SNIP1 gene enc...

HGNC Approved Gene Symbol: SNIP1

Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:37,534,448-37,554,292 (from NCBI)

▼ Description
The SNIP1 gene encodes a transcription regulator that plays a role in several intracellular signaling pathways. SNIP1 also encodes a component of the human activated spliceosome, which plays a role in splicing and retention of pre-mRNA (Ammous et al., 2021).

▼ Cloning and Expression
Using SMAD1 (601595) as bait in a yeast 2-hybrid screen of a fetal brain cDNA library, followed by screening a cardiac cDNA library, Kim et al. (2000) cloned SNIP1. The deduced 396-amino acid protein has a calculated molecular mass of about 50 kD. SNIP1 contains an N-terminal bipartite nuclear localization signal and a C-terminal forkhead (see 164874)-associated domain. Northern blot analysis detected transcripts of 4.4, 2.4, and 1.5 kb in all tissues examined, with highest expression in heart and skeletal muscle. Western blot analysis of several cell lines showed that SNIP1 has an apparent molecular mass of about 50 kD. Western blot analysis of multiple adult mouse tissues detected Snip1 in all tissues examined. Immunohistochemical analysis of rat kidney sections detected Snip1 localized specifically to epithelial elements. Indirect immunofluorescence demonstrated that mouse Snip1 localized to the nucleus in a mouse mammary cell line.

▼ Gene Structure
Kim et al. (2000) determined that the SNIP1 gene contains 4 exons.

▼ Mapping
By genomic sequence analysis, Kim et al. (2000) mapped the SNIP1 gene to chromosome 1p32.3-p32.2.

Gross (2017) mapped the SNIP1 gene to chromosome 1p34.3 based on an alignment of the SNIP1 sequence (GenBank BC027040) with the genomic sequence (GRCh38).

▼ Gene Function
Kim et al. (2000) found that SNIP1 interacted with several SMADs. The C terminus of SNIP1 interacted with SMAD1 and SMAD2 (601366) in a yeast 2-hybrid assay and in mammalian overexpression systems. However, the N terminus of SNIP1 contains binding sites for both SMAD4 (600993) and the coactivators CBP (CREBBP; 600140) and p300 (EP300; 602700). Interaction between endogenous Snip1 and Smad4 or Cbp/p300 was detected in a mouse mammary cell line and in vitro, and binding with p300 required the C/H1 domain of p300. Overexpression of full-length SNIP1 or its N terminus inhibited gene responses to TGF-beta (190180) and CBP/p300 and inhibited the formation of a SMAD4/p300 complex. Furthermore, injection of full-length SNIP1 or N-terminal SNIP1 into Xenopus embryos altered dorsomedial mesoderm formation, including loss of anterior structures.

Kim et al. (2001) found that SNIP1 inhibited nuclear factor kappa-B (NFKB; see 164011), which required the C/H1 domain of CBP/p300 for transcriptional activity. Inhibition of NFKB involved competition between the N-terminal domain of SNIP1 and the NFKB subunit RELA (164014) for binding CBP/p300, as well as direct binding and sequestration of RELA by SNIP1. During mouse embryogenesis, expression of Snip1 overlapped nuclear staining for Rela and p300 in certain tissues. Kim et al. (2001) hypothesized that SNIP1 may regulate access of transcription factors to the coactivators p300 and CBP in select cells and regulate the pattern of gene expression in embryogenesis.

Fujii et al. (2006) found that SNIP1 associated with MYC (190080) and functioned as a regulator of MYC activity in several human cell lines. Mutation analysis showed that the N terminus of MYC bound the C terminus of SNIP1. SNIP1 enhanced the transcriptional activity of MYC both by stabilizing it against proteasomal degradation and by bridging the MYC/p300 complex. Using rodent cells, Fujii et al. (2006) found a synergistic effect of Snip1, Myc, and Ras (190020) in inducing formation of foci in an in vitro transformation assay. SNIP1 was found to stimulate anchorage-independent growth. Immunohistochemical analysis showed SNIP1 expression in many different human cancers. Expression was highest in breast cancers, where 57% of the specimens showed nuclear SNIP1 staining. SNIP1 and MYC were coexpressed in a significant number of non-small cell lung cancers, suggesting that SNIP1 may be a modulator of MYC activity in carcinogenesis.

Ammous et al. (2021) noted that SNIP1 has been identified as a regulator of several transcription factors, including SMADs (see, e.g., SMAD1, 601595), which is involved in the TFGB1 (190180) signaling pathway, NFKB, and MYC. SNIP1 has also been identified as a component of the human activated spliceosome, which plays a role in splicing and retention of pre-mRNA.

▼ Molecular Genetics
By homozygosity mapping followed by exome sequencing of Amish patients with neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures (NEDHCS; 614501), Puffenberger et al. (2012) identified a homozygous mutation in the SNIP1 gene (E366G; 608241.0001). Six heterozygous carriers of this mutation were found among 203 Old Order Amish controls, yielding a population-specific allele frequency of 1.48%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)

Ammous et al. (2021) reported 35 Amish NEDHCS patients who carried a homozygous E366G mutation in the SNIP1 gene. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder within each nuclear family. The findings confirmed a founder effect for this variant. Transcriptome analysis of blood cells derived from 6 individuals showed differential expression of several pathways compared to controls, including TGFB1 (190180) signaling, NOTCH3 (600276) signaling, the MYC (190080) pathway, and genes involved in synaptic vesicles or those implicated in other neurodevelopmental disorders. The findings indicated that this mutation in the SNIP1 gene causes a complex neurodevelopmental disorder likely through alteration of multiple signaling pathways that ultimately influence embryogenesis and neurodevelopment.

▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, CRANIOFACIAL ABNORMALITIES, AND SEIZURES
SNIP1, GLU366GLY
In 3 Amish patients with neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures (NEDHCS; 614501), Puffenberger et al. (2012) identified a homozygous c.1097A-G transition in the SNIP1 gene, resulting in a glu366-to-gly (E366G) substitution in a highly conserved residue in the C terminus. Six heterozygous carriers of this mutation were found among 203 Old Order Amish controls, yielding a population-specific allele frequency of 1.48%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) The mutation was found by homozygosity mapping followed by exome sequencing. Overexpression of the corresponding mutant murine Snip1 (E353G) in mouse inner medullary collecting duct cells showed a more aggregated appearance in the nucleus compared to wildtype, which showed a punctate appearance in the nucleus. Western blot analysis showed decreased levels of the mutant protein, suggesting that it is unstable. Puffenberger et al. (2012) postulated that decreased abundance of SNIP1 likely results in decreased c-Myc (190080) activity and increased TGF-beta (TGFB1; 190180) and NF-kappa-B (NFKB1; 164011) signaling, which may cause abnormal brain and skull development.

Ammous et al. (2021) reported 35 Amish NEDHCS patients who carried a homozygous E366G mutation in the SNIP1 gene. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder within each nuclear family. The findings confirmed a founder effect for this variant. Transcriptome analysis of blood cells derived from 6 individuals showed differential expression of several pathways compared to controls, including TGFB1 (190180) signaling, NOTCH3 (600276) signaling, the MYC (190080) pathway, and genes involved in synaptic vesicles or those implicated in other neurodevelopmental disorders.

Tags: 1p34.3