Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function?
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 (delta7). 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/delta7 ratios due to a decrease in the FL and an increase in delta7 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.
Soler-Botija
Carolina
C
Department of Genetics and Research Institute, Hospital Sant Pau, Barcelona, Spain.
Cuscó
Ivón
I
Caselles
Lídia
L
López
Eva
E
Baiget
Montserrat
M
Tizzano
Eduardo F
EF
D000367:Age Factors; D017398:Alternative Splicing; D015153:Blotting, Western / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003720:Densitometry / Q000379:methods; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000509:alpha-Fetoproteins
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000509:alpha-Fetoproteins