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FLASH GENE

Symbol

SMN1

contributors: shn/npt/pgu - updated : 15-10-2013

HGNC name	survival of motor neuron 1, telomeric
HGNC id	11117

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	anonymous DNA segment
SPECIAL FEATURE	arranged in tandem
text	telomeric copy, part of an inverted duplicated region
STRUCTURE	28.07 kb     9 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	down-regulation of SMN promoter activity during cellular differentiation
	potential binding sites for transcription factors ( Sp1, Ap1, zeste and RXRB )
	nine amino acid motif within exon 2b, PAKKNKSQK, not only playing an integral role in Cajal body targeting, but also encoding the self-association domain.

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D5S1967 - D5S629 - SMN1 - D5S1999 - D5S637 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000344 (transcript variant d) 9 splicing 1641 NP_000335 38 294 throughout cerebral and spinal cord areas - nucleoplasm and cytoplasm of both mature and developing motor neurons 1997 9302277 An isoform of SMN comprising only the amino terminus (exons 13 and a part of intron 3) found only in axons (Setola et al, 2007) NM_022874 (transcript variant b) 8 splicing 1545 NP_075012 28.3 262 throughout cerebral and spinal cord areas - nucleoplasm and cytoplasm of both mature and developing motor neurons 1997 9302277 lacking exon 5 variant a - - - isoform a 18 - . axonal isoform detectable only during motoneuronal development and was down-regulated after birth . in spinal cord and brain 2007 17261814 stop codons truncating the reading frame shortly after the exon 3/intron 3 boundary; FL-SMN and a-SMN have identical N-terminal regions and diverge for the C-terminal tails stimulates axonogenesis

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       highly Nervous brain       highly   spinal cord       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum cardiac     Muscular striatum skeletal     Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol   fibroblast Lymphoid/Immune lymphocyte Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	predominantly, in tissues

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	GEMIN2 binding domain
	self association domain
	lysine rich domain (K-rich)
	Tudor domains bound to symmetric and asymmetric dimethylated arginine (DMA) that is inherent in the RNP complexes (PMID;
	proline-rich domain (P-rich)
	conserved YG box

conjugated

GlycoP

mono polymer

heteromer , oligo

HOMOLOGY

interspecies	ortholog to Smn1, Rattus norvegicus
	ortholog to Smn1, Mus musculus
	ortholog to smn1, Danio rerio

intraspecies

paralog to SMN2

Homologene

FAMILY

important member of the insulin-like growth factor (IGF) system

CATEGORY

signaling cytokine growth factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic,granule
	intracellular,nucleus,nucleoplasm,nuclear bodies,coiled bodies (Cajal)
text	generally located both in the cytoplasm and the nucleus where it is highly associated with gem-like (gemini of coiled bodies) structures
	localizes diffusely throughout the cytoplasm, and in nuclear bodies called Cajal bodies, which are believed to be ribonucleoprotein (RNP) processing and storage sites
	colocalizes in ribonucleoprotein granules within neurites and at growth cones

basic FUNCTION	inhibites the onset of apoptosis in NGF/dBcAMP-deprived or UV-treated co-differentiated PC12 cells by preventing cytochrome c release and caspase-3 activation, indicating that its effects are through suppression of the mitochondrial apoptotic pathway
	role in neurite outgrowth and neuromuscular maturation during neuronal differentiation and development
	role at the neuromuscular junction
	plays a neuron-specific role during development
	enhancer of apoptosis in malignant prostate cells
	playing a key role in neurite outgrowth, via its possible involvement in nucleocytoplasmic and dendritic transport
	important roles in RNA metabolism
	SMN complex activity in snRNP assembly is regulated and point to a differential requirement for SMN function during development and cellular differentiation
	being essential for the biogenesis of small nuclear RNA-ribonucleoproteins, the major components of the pre-mRNA splicing machinery
	implicated in the biogenesis of the spliceosomal small nuclear ribonucleoproteins (snRNPs)
	prolonging the half-life of the IGFs and altering their interaction with cell surface receptors, by binding to the first one
	acting as an inhibitor of IGF-induced bone cell proliferation
	acting as a transport protein for IGF-I and IGF-II and modulating their biological effects
	being a novel dB-cAMP-induced anti-angiogenic and anti-tumorigenic mediator
	enhancing cardiomyocyte differentiation
	a role in axonogenesis
	Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish
	a key role for the SMN complex in RNA metabolism and in splicing regulation indicating that SMA is a general splicing disease that is not restricted to motor neurons
	SMN1-GEMIN2 complex plays a role in homologous recombination, in addition to spliceosomal snRNP assembly
	role of IGFBP4 in regulating IGF bioavailability

CELLULAR PROCESS	cell life, proliferation/growth
	cell life, cell death/apoptosis
	nucleotide, RNA splicing

PHYSIOLOGICAL PROCESS

development , locomotion , nervous system

text	regulation of cell growth
	skeletal system development

PATHWAY

metabolism

signaling

signal transduction

a component	part of the SMN complex (SMN protein and GEMIN2 to 7)
	heteromeric complexes with proteins such as SIP1 and GEMIN4
	forming sub-complexes with gemin proteins, complexes that localise to both stationary and dynamic neurite granules
	SMN1-GEMIN2 complex constitutes part of the large SMN complex, which promotes the assembly of the spliceosomal small nuclear ribonucleoprotein (snRNP)

INTERACTION

DNA

RNA

binding

small molecule

protein	proteins involved in the biogenesis of snRNPs
	survival of motor neuron protein interacting protein 1, SIP1 (
	B-cell CLL/lymphoma 2, BCL2 (
	DEAD (Asp-Glu-Ala-Asp) box polypeptide 20, DDX20 (GEMIN3) (
	STRAP to influencing intracellular localization of SMN1
	SIN3A by its SIN3A-interacting domain to the exon 6 region
	IGF2 more than IGF1
	FZD8 and LRP6
	DNA transactivator FUSE binding protein, FBP (
	small nuclear ribonucleoprotein polypeptides B,-D1, and -D3
	LSM4 homolog, U6 small nuclear RNA associated (S. cerevisiae), LSM4
	LSM6 homolog, U6 small nuclear RNA associated (S. cerevisiae), LSM6
	GAR1 (SMN1 interaction requires the arginine- and glycine-rich domains of both fibrillarin and GAR1 and is defective in SMN mutants found in some SMA patients) (
	osteoclast stimulating factor 1, OSTF1
	zinc finger protein ZPR1
	hnRNP Q proteins
	hnRNP-R and gry-rbp/hnRNP-Q (
	coilin, COIL (
	gem (nuclear organelle) associated protein 4, GEMIN4
	gem (nuclear organelle) associated protein 5, GEMIN5 (
	gem (nuclear organelle) associated protein 6, GEMIN6 (
	gem (nuclear organelle) associated protein 7, GEMIN7 (
	snurportin1, SNUPN and karyopherin (importin) beta 1, KPNB1
	tumor suppressor protein p53, (
	TAF4 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 135kDa, TAF4
	protein phosphatase 4 (formerly X), catalytic subunit, PPP4C (
	processing of precursor 7, ribonuclease P/MRP subunit (S. cerevisiae), POP7 (
	transcription corepressor mSin3A (
	profilin 1, PFN1
	Lsm10 and Lsm11 (
	fragile X mental retardation 1, FMR1
	plastin 3, PLS3. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish
	physically interacted with FZD8, and a Wnt co-receptor, LRP6, and inhibited the binding of WNT3A to FZD8 and LRP6
	ELAVL4 interacts with SMN1 and can rescue spinal muscular atrophy-like neuronal defects
	SMN1 is a novel target of ELK1, and the ETS motifs in the SMN1 promoter are involved in this regulation
	GEMIN2 (
	is directly interacting with profilin2a (PFN2 binds to a stretch of proline residues in SMN, which is heavily impaired by a novel SMN2 missense mutation)
	interferes with the ROCK pathway via PFN2, providing a mechanistic basis to explain axonal defects in SMA pathogenesis
	differentially inhibits angiogenesis induced by distinct growth factor signaling pathways as IGFBP4 inhibited FGF2- and IGF1-stimulated angiogenesis
	SOX9 is a transcriptional regulator of IGFBP4 and SOX9-induced activation of IGFBP4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer
	PAPPA cleaves IGF binding protein IGFBP4 and IGFBP5
	COPA is a SMN1-binding partner, implicating this protein complex in normal SMN1 function, and this interaction serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA
	HNRNPM promotes exon 7 inclusion of SMN1 and SMN2 pre-mRNA through targeting an enhancer on exon 7 through recruiting U2AF2

cell & other

REGULATION

repressed by

late in posnatal life to a basal level, which is then maintained throughout life and this downregulation takes place in the spinal cord earlier than in the brain and coincides with the onset of myelination

Other	coregulated with SIP1
	transcriptional regulation during cellular differentiation and development
	gene modifier ZNF259

ASSOCIATED DISORDERS

corresponding disease(s)

AMCSMA1 , SMA , SMA2 , SMA3 , SMA4

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   amplification     abnormal gene copy number increases the susceptibility to amyotrophic lateral sclerosis

Susceptibility

to amyotrophic lateral sclerosis (ALS)

Variant & Polymorphism other	one copy of SMN1 was associated with an increased risk of developing ALS

Candidate gene
Marker
Therapy target	use of single-stranded oligonucleotides to direct genetic conversion of SMN2 to SMN1 in human cells from SMA patients

ANIMAL & CELL MODELS

	Smn-/- mice died during the peri-implantation stage, whereas transgenic mice harbouring SMN2 in the Smn-/- background showed pathological changes in the spinal cord and skeletal muscles similar to those of SMA patients
	mouse lacking the C-terminus of SMN lack nuclear targeting in the motor neuron of the SMN protein
	Drosophila smn mutant show abnormal motor behavior, excitatory post-synaptic currents are reduced while synaptic motor neuron boutons are disorganized indicating defects at the neuromuscular junction
	Caenorhabditis elegans with deletion of smn-1 display locomotor dysfunction, late larval arrest, reduced lifespan sterility and impaired pharyngeal activity