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Human Molecular Genetics Pages 1531-1536  

The role of the SMN gene in proximal spinal muscular atrophy
Clinical Aspects
Genomic Complexity And Instability At The SMA Locus
Identification Of SMN, The SMA-Determining Gene
Correlation Between Severity And SMN Protein Level In Spinal Muscular Atrophy
Molecular Interactions Of The SMN Protein
Neuromuscular Disorders And RNA Metabolism
Conclusions And Future Directions
Acknowledgements
References

The role of the SMN gene in proximal spinal muscular atrophy

The role of the SMN gene in proximal spinal muscular atrophy

Suzie Lefebvre*, Lydie Bürglen, Jean Frézal, Arnold Munnich and Judith Melki1

Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, IFREM, Institut Necker, Hôpital des Enfants Malades, 149 rue de Sèvres, 75743 Paris cedex 15, France and 1Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, CNRS, BP163, 67404 Illkirch cedex, CU de Strasbourg, France

Received April 4, 1998

Childhood spinal muscular atrophy (SMA) is a common recessive autosomal disorder that results in degeneration of lower motor neurons. The identification of the disease gene, Survival of Motor Neuron (SMN), was a major advance in understanding the molecular basis underlying this devastating neuromuscular disease. This finding has greatly improved the genetic counselling of SMA families. Recently, biochemical studies demonstrated its involvement in the biogenesis of spliceosomal snRNPs, suggesting a critical role of SMN in RNA processing. Surprisingly, other studies showed a putative role of SMN in an anti-apoptotic pathway involving Bcl-2. The function of SMN protein is not fully understood. These observations emphasized the difficulty in elucidating the function of any novel protein. Therefore, multidisciplinary approaches are required to understand the pathogenesis of SMA.

CLINICAL ASPECTS

Proximal spinal muscular atrophies (SMAs) are a group of inherited neuromuscular disorders characterized by the degeneration of spinal motoneurons leading to muscular paralysis with muscular atrophy. They form the second most common fatal autosomal recessive disease after cystic fibrosis, with an incidence of 1 in 10 000 newborns (1-4). SMA exists as a broad spectrum from very severe infantile to very mild chronic forms of disease. The clinical heterogeneity of SMA has prompted the International SMA Consortium to subdivide them into three types according to age at first symptoms and milestones of development (5). Type I SMA is the severe form of Werdnig-Hoffmann disease (6,7) with onset at birth or before 6 months and death of respiratory distress usually within 2 years. Type I SMA patients will never be able to sit or walk due to profound muscular weakness. Children with type II SMA (intermediate form) can sit but cannot stand or walk unaided. Type III SMA (Kugelberg-Welander disease) patients show the first clinical signs after 18 months, evolving to a chronic course (8).

The pathological hallmark of SMA is the loss of motor neurons in the anterior horn of the spinal cord and often in the brainstem, the brain cortex being unaffected. Irrespective of the clinical severity, all three forms of SMA are characterized by diffuse symmetric weakness of proximal muscles and the absence of or a marked decrease in deep reflexes. The electromyographic analyses show muscle denervation with neither sign of sensory denervation nor major alteration of motor nerve conduction velocity. Muscle biopsy confirms the muscle denervation with atrophic and hypertrophic fibres and fibre groupings (9) and shows features of muscle immaturity, suggesting an arrest in development (10,11).

GENOMIC COMPLEXITY AND INSTABILITY AT THE SMA LOCUS

By means of linkage analyses, all three forms of SMA have been mapped to chromosome 5q11.2-13.3 (12-15), suggesting that they are allelic disorders. A high-resolution genetic map contributed to narrowing the SMA-critical region and allowed prenatal diagnosis in SMA families (16,17). The genetic interval was cloned into a yeast artificial chromosome (YAC) contig spanning the SMA locus (18-20). The physical map showed that the SMA gene lies within a region containing specific low copy repeats prone to large-scale deletions. Inherited or de novo deletions were observed in SMA patients (20). De novo rearrangements were identified using polymorphic markers in at least 2% of SMA patients (20,21). Further characterizations of the SMA locus revealed a chromosomal region containing an inverted duplication, each element (~500 kb) containing three genes: the Survival of Motor Neuron (SMN) gene (22), the Neuronal Apoptosis Inhibitory Protein (NAIP; 23) and p44, which encodes a subunit of the basal transcription factor TFIIH (24,25; Fig. 1). Large-scale sequencing analysis confirmed the complexity of the region (26). Interestingly, a region on chromosome 6 (6p21.3) is paralogous with the SMA chromosomal region and contains NAIP but not SMN homologues (27).


Figure 1. The genomic organization of the spinal muscular atrophy chromosomal region. The SMN, NAIP and p44 genes are duplicated into centromeric versions SMNc, NAIPc and p44c. Only the telomeric versions are involved in large scale deletions in patients. Cen, centromere; Tel, telomere.

IDENTIFICATION OF SMN, THE SMA-DETERMINING GENE

Fine analyses of the smallest rearrangements detected in SMA patients allowed identification and characterization of the SMN gene. The telomeric copy of SMN (SMNt) was lacking in 98.6% (226/229) of patients; the remaining three patients carried intragenic mutations (22). The centromeric copy of SMN (SMNc) was present in all patients and absent in 5% of control individuals (22). Similar results were reported in other series of SMA patients (Table 1; 28-32). The identification of additional mutations in SMA patients gave further support to the view that SMNt is the SMA-causing gene (Table 2; 22,28,33-38).

Table 1. Frequency of homozygous deletions in the SMN gene in a large series of SMA patients of different geographic origins
Origin No. of SMA patients (%) No. of control individuals (%) Reference
England 140 (97.8) 152 (0) 29
France 229 (98.6) 246 (0) 22
Germany 191 (90) nd 32
Netherlands 103 (93) nd 30
Taiwan 42 (100) 60 (0) 31
Spain 54 (91) nd 28
Total 759 (95) 458 (0)  
nd, not determined.

Table 2. SMN gene mutations identified in proximal spinal muscular atrophy patients
Mutationa Position in SMNb Number of patients Reference
Y272C Exon 6 1 22
5[prime]ivs 7bp del(-13) Exon 7 1 22
3[prime]ivs 4bp del(+10) Exon 7 2 22,38
432-4bp del stop Exon 3 4 28
811-11bp dupl Exon 6 2 33,38
471-5bp del Exon 3 1 34
G275S Exon 6 1 37
G279V Exon 7 1 35
S262I Exon 6 2 36,47
T274I Exon 6 1 36
E134K Exon 3 1 38
618-1bp ins Exon 4 1 38
aThe mutations are positioned according to the nucleotide sequence of SMN cDNA and its predicted amino acid sequence (22).
bSMN exon 6 is conserved in several divergent SMN orthologues identified in Schizosaccharomyces pombe and Caenorhabditis elegans (35).

The absence of detectable SMNt exon 7 in SMA patients (>95%) provided a direct and accurate genetic test for both diagnostic confirmation and prenatal prediction of SMA (22,30,39). Loss of the SMNt gene was also observed in atypical forms of SMA associated with congenital heart defects or arthrogryposis, in somes cases of congenital axonal neuropathy and in some patients affected with the adult form of SMA (40-44). Rare cases with no detectable SMNt exon 7 (<1%) have been reported in asymptomatic relatives of haploidentical SMA type II and III patients (45,46). The genomic complexity of the region and its high degree of variability has hampered the ability to directly detect SMA carriers (47). The development of such a molecular test should greatly improve the genetic counselling of SMA patients and their relatives.

No phenotype-genotype correlation at the SMN gene locus has been established as shown by SMN exon 7 analysis. Genetic analyses of the SMN, NAIP and p44 genes in a large series of SMA patients revealed that large-scale deletions, including the telomeric versions of these genes, are associated with the type I SMA phenotype (25,48-52). Smaller rearrangements involving the SMNt gene only can also result in a severe phenotype, suggesting that NAIPt and/or p44t deletions are not directly involved in the severity of SMA.

SMN gene testing is based on a single base pair difference between SMNt and SMNc exon 7 at the 3[prime]-end of these genes. The dinucleotide repeat C272 (Ag1-CA) is located within the upstream 5[prime]-end of the SMNt and SMNc genes and can be used to estimate the copy number of these genes (53). Combined analyses of SMN exon 7 and marker C272 revealed an association between the copy number of SMNc and the SMA phenotype (22,25,51,52). In type I SMA patients SMNt exon 7 is absent and a reduced number of loci is detected by marker C272. In type II and III SMA patients SMNt exon 7 is not detected, but the number of loci detected by marker C272 indicates that the loci are still present, suggesting a conversion of the SMNt to the SMNc gene. Further analyses by Southern blot analysis and pulsed field gel electrophoresis showed that absence of the SMN gene in type I SMA is associated with a gene dosage effect, whereas in type III SMA no gene dosage effect was detected (20,22,54).

These observations favoured two different mechanisms that would account for lack of the SMNt gene in SMA patients: a gene deletion in type I SMA and a gene conversion event that would result in an increased number of SMNc copies in type II/III SMA (22,47,51,52,54-56). However, rare cases of severe forms are also associated with an increased number of SMNc copies (no gene deletion), suggesting that other factors may influence the severity of disease (57). It has been proposed that the SMA phenotype could be modified by different kinds of converted SMNc gene, which result from conversion extending to a different part(s) of the SMNt gene (51,54,55, reviewed in ref. 58). Yet, in the majority of cases an increased number of SMNc copies correlates with milder SMA phenotypes, suggesting that the SMNc gene is translated into an at least partially functional protein.

CORRELATION BETWEEN SEVERITY AND SMN PROTEIN LEVEL IN SPINAL MUSCULAR ATROPHY

The SMN gene encodes a novel protein of 294 amino acids with a molecular weight of 38 kDa (22). SMN protein was shown to interact with itself and with RNA-binding proteins (59). Immunolocalization of the SMN protein showed an overall cytoplasmic localization and it is detected in prominent new sub-nuclear bodies called gems, for gemini of coiled bodies (59). Gems are usually found in close vicinity to coiled bodies, which are known to be involved in RNA metabolism. Recently, the SMN protein was shown to form a complex with spliceosomal snRNP proteins (60) and to be involved in the biogenesis of spliceosomal snRNPs (61).

The expression of SMN protein in SMA and control individuals was investigated by western blot and immunohistochemical analyses (62). Immunoblot analyses of total protein extracts from lymphoblastoid cell lines revealed that both the SMNt and SMNc genes were translated into a protein of similar mobility. The relative level of SMN protein was markedly reduced in all type I SMA patients, whereas no apparent alteration was observed in type III SMA patients. This marked reduction was independent of deletion of the neighbouring genes NAIP and p44. This observation provides the first molecular basis for classification of SMA severity. Similar results were reported in cultured fibroblasts (63).

SMN protein expression in human fetal tissues (liver and spinal cord) revealed a decreased amount of SMNc protein in both type I and type III SMA, the level being more reduced in severe than in mild forms of the disease (62). A marked reduction in SMN protein amount was also reported in post-natal spinal cord samples of SMA type I patients (63). These observations suggest that expression and/or stability of the SMN and SMNc gene products are different.

Immunohistochemical analyses of SMN protein showed that motor neurons of the spinal cord from control fetuses have a large amount of cytoplasmic SMN protein and large gems as compared with other cells and tissues (62). In contrast, the SMN protein was absent or markedly reduced in motor neurons of SMA type I and type III fetuses respectively. Gems were occasionally observed in motor neurons of SMA type III fetuses, whereas coiled bodies were consistently detected in the SMA fetuses analysed (62). The study of SMN protein expression in monkey and rat spinal cord sections also showed strong SMN immunoreactivity of motor neurons (64). These studies indicate that the SMNc gene product has some active role in patients and the absence of an SMN gene duplication in mouse (65,66) probably accounts for the early embryonic lethality observed with SMN knock-out mice (67). Further characterization of SMN protein expression during human pre- and post-natal development in control and SMA tissues should contribute to a better knowledge of the effects of SMN mutations.

MOLECULAR INTERACTIONS OF THE SMN PROTEIN

The yeast two-hybrid system is a useful method to screen a large number of cDNA molecules to identify protein-protein interactions (68). Recently, two groups have described the interactions of SMN protein with partners from two cellular pathways, RNA-binding proteins (59-61) and Bcl-2, an anti-apoptotic protein (69).

SMN protein was shown to be tightly associated with a novel protein SIP1 (SMN-interacting protein 1). Both SMN and SIP1 proteins co-localized in the cytoplasm and in the gems (59). In spinal motor neurons of SMA fetuses, the SMN protein and the gems were not detectable (62). Additional experiments provided evidence for the SMN-SIP1 complex being involved in cytoplasmic assembly of the common (Sm) snRNP proteins to spliceosomal snRNAs and with the nuclear import of the snRNP complex (60,61). The likely interaction of SMN protein with RNAs (60) and the identification of a motif for a RNA-binding domain in the Brachidanio rerio SMN orthologue sequence (70) also favour the role of SMN protein in RNA metabolism (reviewed in ref. 71).

Nonetheless, the putative interaction of the SMN protein with factors involved in anti-apoptotic pathways, such as Bcl-2, offers an interesting perspective for a role of the SMN protein in regulation of cellular survival and with NAIP-mediated anti-apoptotic activity (72,73). Further characterization of the SMN and Bcl-2 interaction in target tissues (spinal motor neurons and skeletal muscles) should help in our understanding of why certain neurons are affected in SMA patients while all tissues contain the SMN protein. The involvement of SMN in two distinct cellular pathways raises the question of a putative link between them. Hitherto, however, these exciting results provide no relation between an SMN gene defect and motor neuron degeneration.

NEUROMUSCULAR DISORDERS AND RNA METABOLISM

Myotonic dystrophy (DM) is a muscular disorder that also affects other organ systems, such as heart, endocrine system and brain. The primary genetic defect is a (CTG)n trinucleotide repeat expansion in the 3[prime]-untranslated region of the myotonin protein kinase (DMPK) gene (74-77). The severity of the DM disease correlates with the size of the expansion, but its position is difficult to reconcile with dominant inheritance. Several observations suggested that an alteration in DMPK gene expression alone was not responsible for the complex phenotype and that other genes were involved (78). Recently, it was proposed that the DM physiopathology could be due to nuclear sequestration of (CUG)n triplet repeat RNA-binding proteins and to an alteration in RNA molecules in a tissue-specific manner (79-81).

The recent identification of the poly(A)-binding protein 2 gene (PABP2) as the disease gene for oculopharyngeal muscular dystrophy (OPMD; 82) gives another example of the involvement of RNA metabolism in neuromuscular disorders. OPMD is a genetic disorder with onset in the sixth decade characterized by progressive swallowing problems, eyelid drooping and proximal limb weakness. Muscular biopsies revealed the unique nuclear localization of filament inclusions in skeletal muscle fibres, but the physiopathology of the disease remains unclear. The PABP2 gene is ubiquitously expressed and the protein is exclusively located in the nucleus, where it participates in mRNA polyadenylation (83). Nuclear accumulation of the mutated proteins may be involved in the molecular pathology of OPMD. The involvement of these gene products in very general biological processes contrasts with the clinical specificity of the disorders and further analyses will hopefully provide insights into the impairment of RNA metabolism that causes clinical specificity.

CONCLUSIONS AND FUTURE DIRECTIONS

Identification of the SMN gene as the SMA-causing gene has been an important step toward an understanding of the molecular basis of this devastating neuromuscular disorder. Similarly, analyses of SMNc protein expression provided a molecular basis for the clinical variability of the disease. Therefore, hyperexpression of the SMNc protein could represent a conceivable therapeutic strategy in SMA.

The SMN protein function is not fully understood, but recent advances favour the view that SMN plays a role in RNA metabolism (71). Future studies will hopefully help in elucidating the tissue specificity of the disease. For example, a defect(s) in molecular interactions of SMN with a protein(s) and/or RNA(s) specific to the spinal cord could account for degeneration of the spinal motor neurons. Similarly, the role of SMN in biogenesis of spliceosomal components should prompt a search for aberrant maturation of RNA transcripts in a development- and/or tissue-specific manner. Insights into SMN function(s) and the creation of an animal model using conditional mutagenesis of the SMN gene should contribute to an understanding of the pathogenesis of the disease and will help in devising therapeutic approaches in SMA.

ACKNOWLEDGEMENTS

We thank the patients, families and doctors who have contributed to this project and without whom this review would not have been possible, the members of the International SMA Consortium for stimulating discussions, and Solange Bertrandy, Philippe Burlet, Olivier Clermont, Qing Liu and Gideon Dreyfuss for pleasant and fruitful collaborations. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association Française contre les Myopathies (AFM), the Actions Concertées-Science du Vivant (ACC-SV2), the Institut Electricite Santé, the Groupement de Recherches et d'Etudes sur les Génomes (GREG) and the Programme Hospitalier de Recherches Clinique.

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*To whom correspondence should be addressed. Tel: +33 1 44 49 51 63; Fax: +33 1 47 34 85 14; Email: lefebvre@necker.fr

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