SMN2

Official Full Name

survival of motor neuron 2, centromeric

Organism

Homo sapiens

GeneID

6607

Background

This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The full length protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Four transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Sep 2008]

Synonyms

SMNC; BCD541; GEMIN1; TDRD16B; C-BCD541;

Protein Sequence

MAMSSGGSGGGVPEQEDSVLFRRGTGQSDDSDIWDDTALIKAYDKAVASFKHALKNGDICETSGKPKTTPKRKPAKKNKSQKKNTAASLQQWKVGDKCSAIWSEDGCIYPATIASIDFKRETCVVVYTGYGNREEQNLSDLLSPICEVANNIEQNAQENENESQVSTDESENSRSPGNKSDNIKPKSAPWNSFLPPPPPMPGPRLGPGKPGLKFNGPPPPPPPPPPHLLSCWLPPFPSGPPIIPPPPPICPDSLDDADALGSMLISWYMSGYHTGYYMGFRQNQKEGRCSHSLN

Open

Disease

Muscular atrophy

Approved Drug

2 +

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

SMN2 (Survival of Motor Neuron 2) gene is located on human chromosome 5q13.2 and is a highly homologous copy of the SMN1 gene, sharing 99% sequence identity. Together, they form an approximately 500 kb inverted repeat genomic region. This complex genomic structure makes it prone to recombination and deletion events, leading to the occurrence of Spinal Muscular Atrophy (SMA). From a molecular evolutionary perspective, SMN2 is a gene copy unique to primates, while other mammals have only one SMN gene. This genetic feature provides a unique opportunity for disease-modifying treatments for SMA. Despite the high conservation between SMN2 and SMN1 in their coding sequences, there is a key difference between the two in exon 7: a single nucleotide substitution (c.840C>T) in SMN2 alters the pre-messenger RNA splicing pattern, leading to approximately 90% of SMN2 transcripts lacking exon 7 (SMNΔ7) and only 10% producing full-length functional protein. This subtle but critical difference prevents SMN2 from fully compensating for the loss of SMN1 function, forming the molecular basis for SMA pathogenesis.

Figure 1. SMN genes in chromosome 5q13. (Nishio H, et al., 2023)

At the cellular biology level, the SMN protein is a core component of the small nuclear ribonucleoprotein (snRNP) biogenesis complex. This complex catalyzes the assembly of Sm proteins (composed of SNRPB, SNRPD1-3, SNRPE, SNRPF, and SNRPG) onto the Sm site of snRNA, forming the core structural unit of the spliceosome. The SMN complex includes SMN protein, GEMIN2-8, and UNRIP, with SMN serving as the structural scaffold to co-recruit Sm protein subunits, ensuring correct snRNP assembly. Additionally, SMN protein participates in RNA-DNA hybrid (R-loop) resolution during transcription termination, influencing mRNA processing quality. SMN protein exhibits dynamic distribution within cells: it participates in snRNP assembly in the cytoplasm and accumulates in nuclear substructures called Gems (Gemini of Cajal bodies), adjacent to Cajal bodies, where it collaborates in regulating snRNP maturation and transport.

Pathological Mechanisms and Modifier Effects

When the SMN1 gene undergoes homozygous deletion or mutation, SMN2 becomes the sole source of functional SMN protein, with its expression level directly determining the SMA disease phenotype. As an autosomal recessive inherited disease, SMA has an incidence of approximately 1/10,000 in newborns and is the leading genetic cause of death in children under 2 years old. SMA is classified into four types based on age of onset and achievement of motor milestones: Type I (Werdnig-Hoffmann disease) is the most severe, with onset within 6 months, inability to sit independently, and most patients die from respiratory failure before age 2; Type II has onset between 6-18 months, patients can sit but cannot stand independently; Type III (Kugelberg-Welander disease) has onset after 18 months, patients can walk independently but progressively lose motor abilities; Type IV has adult onset with mild symptoms.

The SMN2 copy number is the most important factor in modifying the SMA phenotype. Studies have shown that 88.3% of Type I SMA patients carry only 1 copy of SMN2, while 40.6% of Type II patients carry 2 copies. In contrast, the probability of patients with 3 or 4 copies developing Type I is less than 5%. This dose-dependent effect arises because an increase in SMN2 gene copy number can elevate full-length SMN protein expression levels, partially compensating for the loss of SMN1 function. However, SMN2 copy number is not linearly correlated with phenotype severity. Approximately 4% of SMA patients carry non-5q pathogenic genes (such as UBE1, DYNC1H1, BICD2, etc.), resulting in SMA IV or atypical phenotypes with autosomal dominant, recessive, or X-linked inheritance patterns, reflecting the clinical and genetic heterogeneity of the disease.

At the molecular pathological mechanism level, the lack of SMN protein leads to the degeneration of anterior horn α-motor neurons, resulting in progressive muscle weakness and atrophy. However, SMA is a multi-system disorder, affecting not only motor neurons but also peripheral nerves, neuromuscular junctions, skeleton, heart, liver, and pancreas. Animal model studies have shown that motor neurons have special susceptibility to SMN protein deficiency. When SMN protein levels drop below 50% of normal, neuromuscular junction dysfunction and axonal degeneration occur. This selective susceptibility may be related to the high activity of synaptic transmission in motor neurons and their high protein turnover demands. Furthermore, SMN participates in axonal mRNA transport and local translation, and its deficiency leads to abnormalities in presynaptic terminal structures at neuromuscular junctions, disrupting neuromuscular signaling.

Reference

Butchbach MER. Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development. Int J Mol Sci. 2021 Jul 23;22(15):7896.
Nishio H, Niba ETE, Saito T, et al. Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment. Int J Mol Sci. 2023 Jul 26;24(15):11939.

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