TY - JOUR
T1 - A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2
AU - Monani, Umrao R.
AU - Lorson, Christian L.
AU - Parsons, D. William
AU - Prior, Thomas W.
AU - Androphy, Elliot J.
AU - Burghes, Arthur H.M.
AU - McPherson, John D.
N1 - Funding Information:
We thank Patty McAndrew for providing us with patient DNA samples and SMN copy number data. Support for this work came from Families of SMA and the Muscular Dystrophy Association of America, and NIH grant NS38650. The authors wish to thank the genome sequencing center, Washington University, St Louis for communication of DNA sequence prior to publication.
PY - 1999
Y1 - 1999
N2 - Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telomeric survival motor neuron 1 (SMN1) gene. Alterations within an almost identical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produce no known phenotypic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encoded amino acids. At the genomic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes has not been determined. Thus, differences which might explain why SMN1 is the SMA gene are not readily apparent. In this study, we have completely sequenced and compared genomic clones containing the SMN genes. The two genes show striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an ~ 32 kb region between the two SMN genes is the C→T base change 6 bp inside exon 7. This alteration but not other variations in the SMN genes affects the splicing pattern of the genes. The majority of the transcript from the SMN1 locus is full length, whereas the majority of the transcript produced by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA.
AB - Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telomeric survival motor neuron 1 (SMN1) gene. Alterations within an almost identical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produce no known phenotypic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encoded amino acids. At the genomic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes has not been determined. Thus, differences which might explain why SMN1 is the SMA gene are not readily apparent. In this study, we have completely sequenced and compared genomic clones containing the SMN genes. The two genes show striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an ~ 32 kb region between the two SMN genes is the C→T base change 6 bp inside exon 7. This alteration but not other variations in the SMN genes affects the splicing pattern of the genes. The majority of the transcript from the SMN1 locus is full length, whereas the majority of the transcript produced by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA.
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U2 - 10.1093/hmg/8.7.1177
DO - 10.1093/hmg/8.7.1177
M3 - Article
C2 - 10369862
AN - SCOPUS:0032799998
SN - 0964-6906
VL - 8
SP - 1177
EP - 1183
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
ER -