Implication of Fetal SMN2 Expression in Type I SMA Pathogenesis: Protection or Pathological Gain of Function?

• Published in: Journal of neuropathology and experimental neurology Vol. 64; no. 3; pp. 215 - 223
• Main Authors: Soler-Botija, Carolina, Cuscó, Ivón, Caselles, Lídia, López, Eva, Baiget, Montserrat, Tizzano, Eduardo F
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01-03-2005; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Age Factors; alpha-Fetoproteins; Alternative Splicing; Biological and medical sciences; Blotting, Western - methods; Carbohydrates (enzymatic deficiencies). Glycogenosis; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Densitometry - methods; Diseases of striated muscles. Neuromuscular diseases; Errors of metabolism; Exons; Female; Fibroblasts - metabolism; Gene Expression - genetics; Gene Expression Regulation, Developmental - genetics; Humans; Immunohistochemistry - methods; Kidney - metabolism; Male; Medical sciences; Metabolic diseases; Muscles - cytology; Muscles - embryology; Muscles - metabolism; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - physiopathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; SMN Complex Proteins; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; Human; Neuromuscular diseases; Nervous system diseases; Pathogenesis; Spinal amyotrophy; Human development; Spinal muscular atrophy; Central nervous system disease; Development; SMN2; Fetus; Degenerative disease; Spinal cord disease; Protection
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/64.3.215

Spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. Most of the SMN1 transcript is full-length, whereas a substantial proportion of the SMN2 transcript lacks exon 7 (Δ7). We characterized the developmental expression of SMN2 by comparing control and SMA fetuses. The control spinal cord revealed the highest amount of FL SMN, most of which was of SMN1 origin. When analyzing the SMA spinal cord transcripts, we detected a considerable reduction in the FL/Δ7 ratios due to a decrease in the FL and an increase in Δ7 isoform. After immunoblot and immunohistochemistry analyses, we found that the amount of SMN2 protein in the SMA spinal cord and muscle was lower than in the controls. However, the results of the expression of SMN2 in intestine, lung, adrenal gland, kidney, and eye, which are unaffected by the disease, were the same in controls and SMA samples. In these tissues, SMN2 may compensate for the absence of SMN1, whereas in SMA motor neurons, a cell-specific dysregulation of the SMN2 expression could favor the onset of the acute form of the disease.