SMN2 Gene

📖 Wiki Page

gene1286 wordssynced 2026-04-02

SMN2 Gene

...

SMN2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SMN2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SMN2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Survival of Motor Neuron 2, Telomeric</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q13.2 (Chr5: 70,287,588-70,345,635)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6609</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>601627</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000120247</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q16637</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Survival of Motor Neuron protein</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>294 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~32 kDa</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Spinal cord</td>
<td>Highest</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High</td>
</tr>
<tr>
<td class="label">Skeletal muscle</td>
<td>High</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Low</td>
</tr>
<tr>
<td class="label">SMN2 Copies</td>
<td>Expected Phenotype</td>
</tr>
<tr>
<td class="label">0</td>
<td>No functional SMN - embryonic lethal</td>
</tr>
<tr>
<td class="label">1</td>
<td>Severe SMA (Type 0) - neonatal death</td>
</tr>
<tr>
<td class="label">2</td>
<td>Severe SMA (Type I) - onset before 6 months</td>
</tr>
<tr>
<td class="label">3</td>
<td>Intermediate (Type II/III) - onset 6-18 months</td>
</tr>
<tr>
<td class="label">4+</td>
<td>Mild/Adult-onset (Type III/IV) - later onset</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Nusinersen</td>
<td>Intronic splicing silencer (ISS)</td>
</tr>
<tr>
<td class="label">Risdiplam</td>
<td>SMN2 pre-mRNA</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>SMN1 gene replacement</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">6 edges</a></td>
</tr>
</table>

Survival of Motor [Neuron](/entities/neurons) 2, Telomeric - SMN2 is a paralog of SMN1 that encodes the Survival of Motor Neuron protein, critical for spliceosomal function and motor neuron survival.

Overview

Mermaid diagram (expand to render)

Introduction

The SMN2 gene is a paralog of SMN1 located on chromosome 5q13.2. While SMN1 is the primary source of functional SMN protein, SMN2 serves as a disease modifier in spinal muscular atrophy (SMA). The SMN2 gene differs from SMN1 by a critical C→T transition at position 6 of exon 7, which causes exon 7 skipping during splicing, resulting in the production of a truncated and unstable protein (SMNΔ7) instead of full-length functional SMN protein[@lefebvre1995].

Despite producing mostly defective protein, SMN2 copy number significantly influences SMA severity - this discovery became the foundation for all SMA therapeutics that work by enhancing SMN2 splicing or expression. Understanding SMN2 biology is essential for developing new treatments for SMA and potentially other neurodegenerative diseases[@lorson1999].

Function

Molecular Function

SMN2 encodes the Survival of Motor Neuron (SMN) protein, which is essential for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). The SMN complex plays a critical role in pre-mRNA splicing by facilitating the biogenesis of U1, U2, U4, and U5 snRNPs[@pellizzoni2002].

Core Functions

SMN Complex Assembly: Forms the core of the SMN complex with Gemin2-8 and UNRIP

snRNP Biogenesis: Required for cytoplasmic assembly of snRNPs

Pre-mRNA Splicing: Facilitates proper splicing of U1, U2, U4, and U5 snRNPs

Gem Formation: Functions in nuclear gem (Gemini of coiled bodies) formation

snRNA Modification: Guides 2'-O-methylation of snRNAs

Splicing Regulation

The key difference between SMN1 and SMN2 is the splicing of exon 7:

SMN1: Efficiently includes exon 7 → full-length SMN protein
SMN2: C→T transition at position +6 of exon 7 disrupts an exonic splice enhancer (ESE), causing exon 7 skipping in ~90% of transcripts → SMNΔ7 (truncated, unstable)

Expression Pattern

Ubiquitously expressed in all tissues
Highest expression: Brain, spinal cord, skeletal muscle
Developmental regulation: High during embryonic development, decreases postnatally
Cellular localization: Nuclear and cytoplasmic

Tissue Distribution

Disease Associations

Spinal Muscular Atrophy (SMA)

SMA is an autosomal recessive neuromuscular disorder caused by deletion or mutation of SMN1, with SMN2 serving as the major disease modifier[@finkel2017].

SMN2 Copy Number and Phenotype

Pathophysiology

SMN deficiency leads to:

Impaired snRNP assembly
Defective pre-mRNA splicing
Widespread splicing alterations
Motor neuron dysfunction and death
Muscle atrophy

ALS (Amyotrophic Lateral Sclerosis)

Recent research suggests SMN deficiency may contribute to ALS pathogenesis[@mendell2017]:

Reduced SMN levels in ALS patients
Motor neuron vulnerability linked to SMN dysfunction
Overlap between SMA and ALS mechanisms
Clinical trials exploring SMN-enhancing therapies in ALS

Other Neurological Conditions

Spinal muscular atrophy with respiratory distress (SMARD1): Caused by IGHMBP2 mutations, shares features with SMA
Congenital myastheric syndrome: SMN-related synaptic dysfunction
X-linked SMA: Rare form associated with SMN1 mutations

Therapeutic Targeting

FDA-Approved Treatments

All three FDA-approved SMA therapies target SMN2 to increase functional SMN protein production[@baranello2021]:

1. Nusinersen (Spinraza)

Mechanism: Antisense oligonucleotide (ASO) modifying SMN2 splicing
Delivery: Intrathecal (lumbar puncture)
Dosing: Loading dose (4 doses) then maintenance every 4 months
Efficacy: Significant improvement in motor function, approved for all ages

2. Onasemnogene Abeparvovec (Zolgensma)

Mechanism: AAV9 vector delivering functional SMN1 gene
Delivery: Single intravenous infusion
Efficacy: One-time treatment with long-term benefits
Approved for: Patients under 2 years of age

3. Risdiplam (Evrysdi)

Mechanism: Small molecule splicing modifier
Delivery: Oral (daily)
Efficacy: Increases SMN protein in blood and CNS
Approved for: Patients 2 months and older

Mechanism Details

Clinical Trials

Combination therapies: Nusinersen + gene therapy, nusinersen + risdiplam
Newborn screening: Early intervention critical for optimal outcomes
Adult SMA: Ongoing trials for long-term efficacy
Broader applications: Trials in ALS, other neuromuscular disorders

Animal Models

Mouse Models

Smn-/-: Embryonic lethal
Smn-/-;SMN2/+: Severe SMA phenotype
SMNΔ7: Model for Type I SMA

Therapeutic Testing

All three FDA-approved therapies validated in mouse models
Gene therapy: Dramatic rescue of SMA mice
Antisense oligonucleotides: Improved survival and motor function
Small molecules: Enhanced SMN expression and function

Research Directions

Understanding exon 7 splicing: New modifiers and enhancers
Non-SMN functions: Exploring SMN-independent mechanisms
CNS delivery: Improving brain penetration of therapies
Biomarkers: Developing markers for treatment response
Long-term outcomes: Tracking patients into adulthood

Key Publications

Lefebvre S, et al. "Identification and characterization of a spinal muscular atrophy-determining gene." Cell. 1995;80(1):155-165. PMID: 10471481(https://pubmed.ncbi.nlm.nih.gov/10471481/)

Lorson CL, et al. "A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy." Proc Natl Acad Sci. 1999;96(11):6307-6311. PMID: 10339583(https://pubmed.ncbi.nlm.nih.gov/10339583/)

Pellizzoni L, et al. "Essential role for the SMN complex in the assembly of snRNPs." Curr Opin Cell Biol. 2002;14(3):301-306. PMID: 12069851(https://pubmed.ncbi.nlm.nih.gov/12069851/)

Finkel RS, et al. "Nusinersen in infants with SMA." N Engl J Med. 2017;377(18):1723-1732. PMID: 29091557(https://pubmed.ncbi.nlm.nih.gov/29091557/)

Mendell JR, et al. "Gene therapy for SMA." N Engl J Med. 2017;377(18):1713-1722. PMID: 29091556(https://pubmed.ncbi.nlm.nih.gov/29091556/)

Baranello G, et al. "Risdiplam in Type 1 SMA." N Engl J Med. 2021;384(10):915-923. PMID: 33761207(https://pubmed.ncbi.nlm.nih.gov/33761207/)

Background

The study of Smn2 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[NCBI Gene: SMN2](https://www.ncbi.nlm.nih.gov/gene/6609)
[UniProt: Q16637](https://www.uniprot.org/uniprot/Q16637)
[OMIM: 601627](https://www.omim.org/entry/601627)
[Cure SMA Foundation](https://www.curesma.org/)
[SMA Foundation](https://smafoundation.org/)
[SMN Complex Structure (PDB)](https://www.ebi.ac.uk/pdbe/entry/pdb/6exn)

References

[Lefebvre S, et al, "Identification and characterization of a spinal muscular atrophy-determining gene." Cell (1995)](https://pubmed.ncbi.nlm.nih.gov/10471481/)

[Lorson CL, et al, "A single nucleotide in the SMN gene regulates splicing." Proc Natl Acad Sci (1999)](https://pubmed.ncbi.nlm.nih.gov/10339583/)

[Pellizzoni L, et al, "Essential role for the SMN complex in the assembly of snRNPs." Curr Opin Cell Biol (2002)](https://pubmed.ncbi.nlm.nih.gov/12069851/)

[Finkel RS, et al, "Nusinersen in infants with SMA." N Engl J Med (2017)](https://pubmed.ncbi.nlm.nih.gov/29091557/)

[Mendell JR, et al, "Gene therapy for SMA." N Engl J Med (2017)](https://pubmed.ncbi.nlm.nih.gov/29091556/)

[Baranello G, et al, "Risdiplam in Type 1 SMA." N Engl J Med (2021)](https://pubmed.ncbi.nlm.nih.gov/33761207/)

Pathway Diagram

The following diagram shows the key molecular relationships involving SMN2 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

SMN2 Gene

SMN2 Gene

SMN2 Gene

Overview

Introduction

Function

Molecular Function

Core Functions

Splicing Regulation

Expression Pattern

Tissue Distribution

Disease Associations

Spinal Muscular Atrophy (SMA)

SMN2 Copy Number and Phenotype

Pathophysiology

ALS (Amyotrophic Lateral Sclerosis)

Other Neurological Conditions

Therapeutic Targeting

FDA-Approved Treatments

1. Nusinersen (Spinraza)

2. Onasemnogene Abeparvovec (Zolgensma)

3. Risdiplam (Evrysdi)

Mechanism Details

Clinical Trials

Animal Models

Mouse Models

Therapeutic Testing

Research Directions

Key Publications

Background

See Also

External Links

References

Pathway Diagram