A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy

Christian L. Lorson, Eric Hahnen, Elliot Androphy, Brunhilde Wirth

Research output: Contribution to journalArticle

895 Citations (Scopus)

Abstract

SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNΔ7 is partially defective for self- association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.

Original languageEnglish (US)
Pages (from-to)6307-6311
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number11
DOIs
StatePublished - May 25 1999
Externally publishedYes

Fingerprint

Spinal Muscular Atrophy
Exons
Nucleotides
Genes
Alternative Splicing
Motor Neurons
Codon
Molecular Biology
Cultured Cells
Alleles
Mutation
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. / Lorson, Christian L.; Hahnen, Eric; Androphy, Elliot; Wirth, Brunhilde.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 11, 25.05.1999, p. 6307-6311.

Research output: Contribution to journalArticle

@article{1cc44ad02a1f43cc946c6305e2166d22,
title = "A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy",
abstract = "SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNΔ7 is partially defective for self- association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.",
author = "Lorson, {Christian L.} and Eric Hahnen and Elliot Androphy and Brunhilde Wirth",
year = "1999",
month = "5",
day = "25",
doi = "10.1073/pnas.96.11.6307",
language = "English (US)",
volume = "96",
pages = "6307--6311",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "11",

}

TY - JOUR

T1 - A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy

AU - Lorson, Christian L.

AU - Hahnen, Eric

AU - Androphy, Elliot

AU - Wirth, Brunhilde

PY - 1999/5/25

Y1 - 1999/5/25

N2 - SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNΔ7 is partially defective for self- association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.

AB - SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNΔ7 is partially defective for self- association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.

UR - http://www.scopus.com/inward/record.url?scp=0033033434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033033434&partnerID=8YFLogxK

U2 - 10.1073/pnas.96.11.6307

DO - 10.1073/pnas.96.11.6307

M3 - Article

VL - 96

SP - 6307

EP - 6311

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 11

ER -