Characteristics of genetic changes in the <i>SMN1</i> gene in spinal muscular atrophy 5q

Abstract

Background. Proximal spinal muscular atrophy 5q (5q‑SMA) is one of the most common neuromuscular diseases, which is caused by mutations of the SMN1 gene. Despite the fact that most studies consider SMN1 “deletion” as the most common cause of 5q‑SMA, gene loss is in fact associated with both classical deletions and conversions of SMN1 and SMN2, as well as with formation of chimeric structures. Up to now, far too little attention has been paid to the prevalence of types of SMN1 loss. However, different types of mutations can have different influence on the clinical findings and the effectiveness of therapy. A deeper study of the structure of these genes will allow us to determine the predictors of response to treatment and bring us closer to understanding the reasons for the instability of the SMN region.Aim. To study genetic changes in the SMN1 gene, as well as the number of copies of the SMN1 and SMN2 genes in 5q‑SMA.Materials and methods. The study involved 703 patients, for whom the analysis of the number of copies of SMN1 and SMN2 was performed in the center of molecular medicine of I.P. Pavlov First Saint Petersburg State Medical University for 2018–2021. Gene copy number analysis was performed by multiplex ligation‑dependent probe amplification (MLPA) using the SALSA MLPA P021 SMA kit (MRC Holland).Results. Among 703 participants, a homozygous SMN1 deletion was found in 167 (24 %), 76 (11 %) were carriers of the deletion and no aberrations were found in the remaining 460 (65 %). Among patients with a homozygous deletion, 41 (24 %) cases of a true deletion were identified. Also, 11 (7 %) cases of partial deletion with a homozygous loss of the 7th exon and heterozygous of the 8th exon of SMN1 were identified. The most common type of aberration was the conversion of SMN1 to SMN2 – 94 (56 %) cases, which is characterized by a homozygous loss of SMN1 and a reciprocal increase in SMN2 copies. In addition, 21 (13 %) cases of the formation of hybrid genes were found.Conclusion. Types of genetic aberrations in 5q‑SMA have not been studied enough yet. A search of the literature revealed very few studies which results are comparable with ours. However, further research of genetic changes in SMN1 and SMN2 might bring more clarity on the causes and mechanisms of this disease, and get us closer to finding the most effective method of treatment.

Keywords

• spinal muscular atrophy
• smn1
• smn2
• molecular diagnostics
• pathogenetic therapy
• gene therapy