A man in his early 30s suddenly developed weakness in hishands and neck, followed weeks later by burning musclepain—all symptoms of late-onset muscular dystrophy. Hisinternist ordered genetic tests to determine whether he had oneof the most common adult-onset muscular dystrophies—myotonicdystrophy type 1 (DM1) or myotonic dystrophy type 2 (DM2). Thetests detect mutations in the DMPK and CNBP genes, the onlygenes known to be associated with DM1 and DM2. While awaitingthe results of the gene tests, the internist explained that thedisease-causing mutations in these genes do not result in changesto the coding sequence. Rather, myotonic dystrophies resultfrom increased, or expanded, numbers of tri- and tetranucleotiderepeats in the 3 untranslated region of the DMPK or CNBP genes.The doctor went on to explain that the presence of RNAs withexpanded numbers of repeats leads to aberrant alternative splicingof other mRNAs, causing widespread disruption of cellular pathways.This discussion raises a number of interesting questions. What is alternative splicing, where does it occur, and howcould disrupting it affect the expression of the affectedgene(s)?
A man in his early 30s suddenly developed weakness in his
hands and neck, followed weeks later by burning muscle
pain—all symptoms of late-onset muscular dystrophy. His
internist ordered genetic tests to determine whether he had one
of the most common adult-onset muscular dystrophies—myotonic
dystrophy type 1 (DM1) or myotonic dystrophy type 2 (DM2). The
tests detect mutations in the DMPK and CNBP genes, the only
genes known to be associated with DM1 and DM2. While awaiting
the results of the gene tests, the internist explained that the
disease-causing mutations in these genes do not result in changes
to the coding sequence. Rather, myotonic dystrophies result
from increased, or expanded, numbers of tri- and tetranucleotide
repeats in the 3 untranslated region of the DMPK or CNBP genes.
The doctor went on to explain that the presence of RNAs with
expanded numbers of repeats leads to aberrant alternative splicing
of other mRNAs, causing widespread disruption of cellular pathways.
This discussion raises a number of interesting questions.
What is alternative splicing, where does it occur, and how
could disrupting it affect the expression of the affected
gene(s)?
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