Myotonic Dystrophy
From Iusmgenetics
(Difference between revisions)
(Created page with '==Myotonic Dystrophy== ===General background information=== *'''Most common inherited neuromuscular disorder of adult life''' ===Mode of inheritance=== *'''Autosomal dominant''…') |
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*Demonstrates '''anticipation''' | *Demonstrates '''anticipation''' | ||
*Because of anticipation and instability, ''and because there is more expansion in female gametogenesis'' '''the most severe forms (congenital myotonic dystrophy) are transmitted by the mother'''. | *Because of anticipation and instability, ''and because there is more expansion in female gametogenesis'' '''the most severe forms (congenital myotonic dystrophy) are transmitted by the mother'''. | ||
| + | *The most severe form (Congential Myotonic Dystrophy) comes from '''maternal inheritance''' because '''female gametogenesis lends itself to the worst expansion of repeats'''. | ||
===Single important gene=== | ===Single important gene=== | ||
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===Etiology=== | ===Etiology=== | ||
| - | *'''CTG repeats accumulate in the 3' UTR region'''. | + | *'''CTG repeats accumulate in the 3' UTR region''' of the DMPK protein (DM protein kinase). |
**There are usually 5-35 repeats in the 3' UTR of the dmpk gene. | **There are usually 5-35 repeats in the 3' UTR of the dmpk gene. | ||
*Myotonic dystrophy manifests in pts with '''> 50 repeats'''. | *Myotonic dystrophy manifests in pts with '''> 50 repeats'''. | ||
| - | *NB: the protein sequence is normal! | + | *'''NB: the protein sequence is normal!''' |
*Myotonic dystrophy demonstrates '''instability''' and '''anticipation'''. | *Myotonic dystrophy demonstrates '''instability''' and '''anticipation'''. | ||
| + | *Note that ''instability occurs in both somatic and germline cells''. | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
*There is probably less DMPK protein but '''myotonic dystrophy is a disease of RNA accumulation''', primarily. | *There is probably less DMPK protein but '''myotonic dystrophy is a disease of RNA accumulation''', primarily. | ||
| + | **Therefore, this is not a disease of haploinsufficiency as much as it is about a "gain of (negative) function" (namely accumulation of RNA). | ||
| + | **DPMK knockout mice don't display the MD phenotype but mice with a repeat expansion do show the phenotype. | ||
*As repeats expand, the RNA transcript becomes less apt to be translated and less apt to degraded so it accumulates. | *As repeats expand, the RNA transcript becomes less apt to be translated and less apt to degraded so it accumulates. | ||
| + | **Accumulation of the DMPK RNA occurs primarily in the nucleus. | ||
| + | |||
| + | |||
| + | *DPMK knockout mice don't display the MD phenotype but mice with a repeat expansion do show the phenotype. | ||
| + | **Even when the expansion is in a different location in the dpmk gene, the phenotype is displayed (myotonia). | ||
*Accumulated DMPK RNA has been shown to cause '''aberrant splicing of CIC-1 pre-mRNA''' which '''leads to hyperexcitability of skeletal muscle'''. | *Accumulated DMPK RNA has been shown to cause '''aberrant splicing of CIC-1 pre-mRNA''' which '''leads to hyperexcitability of skeletal muscle'''. | ||
**CIC-1 is the main chloride channel in skeletal muscle. | **CIC-1 is the main chloride channel in skeletal muscle. | ||
| + | **These experiments were in mice. | ||
| + | **This concept that a gain of triplet expansion can lead to negative affects on many different protein RNA molecules is called a '''trans-dominant effect'''. | ||
*This "toxic RNA" is called a '''trans-dominant effect: one in which excess of a product (in this case RNA) gives it a gain-of-negative-function.''' | *This "toxic RNA" is called a '''trans-dominant effect: one in which excess of a product (in this case RNA) gives it a gain-of-negative-function.''' | ||
*This is the first well-documented example of this pathogenic mechanism in humans. | *This is the first well-documented example of this pathogenic mechanism in humans. | ||
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| - | *There is a second gene that can have a similar "trans-dominant effect": | + | *There is a second gene that can have a similar "trans-dominant effect": znf9 = dm2 |
**'''Expansions in ZNF9 cause myotonic dystrophy type 2 (DM2).''' | **'''Expansions in ZNF9 cause myotonic dystrophy type 2 (DM2).''' | ||
**The repeat expansion in ZNF9 (DM2) is "CCUG" (a quartet repeat) in the first intron. | **The repeat expansion in ZNF9 (DM2) is "CCUG" (a quartet repeat) in the first intron. | ||
| - | **ZNF9 expansions generate only a small percentage of myotonic distrophy cases. | + | **ZNF9 expansions '''generate only a small percentage of myotonic distrophy cases'''. |
**ZNF9 mRNA accumulation interrupts proper RNA processing of other genes. | **ZNF9 mRNA accumulation interrupts proper RNA processing of other genes. | ||
Current revision as of 12:31, 28 November 2011
Contents |
[edit] Myotonic Dystrophy
[edit] General background information
- Most common inherited neuromuscular disorder of adult life
[edit] Mode of inheritance
- Autosomal dominant
- Demonstrates anticipation
- Because of anticipation and instability, and because there is more expansion in female gametogenesis the most severe forms (congenital myotonic dystrophy) are transmitted by the mother.
- The most severe form (Congential Myotonic Dystrophy) comes from maternal inheritance because female gametogenesis lends itself to the worst expansion of repeats.
[edit] Single important gene
- dmpk: dystrophia myotonica protein kinase
[edit] Etiology
- CTG repeats accumulate in the 3' UTR region of the DMPK protein (DM protein kinase).
- There are usually 5-35 repeats in the 3' UTR of the dmpk gene.
- Myotonic dystrophy manifests in pts with > 50 repeats.
- NB: the protein sequence is normal!
- Myotonic dystrophy demonstrates instability and anticipation.
- Note that instability occurs in both somatic and germline cells.
[edit] Pathogenesis
- There is probably less DMPK protein but myotonic dystrophy is a disease of RNA accumulation, primarily.
- Therefore, this is not a disease of haploinsufficiency as much as it is about a "gain of (negative) function" (namely accumulation of RNA).
- DPMK knockout mice don't display the MD phenotype but mice with a repeat expansion do show the phenotype.
- As repeats expand, the RNA transcript becomes less apt to be translated and less apt to degraded so it accumulates.
- Accumulation of the DMPK RNA occurs primarily in the nucleus.
- DPMK knockout mice don't display the MD phenotype but mice with a repeat expansion do show the phenotype.
- Even when the expansion is in a different location in the dpmk gene, the phenotype is displayed (myotonia).
- Accumulated DMPK RNA has been shown to cause aberrant splicing of CIC-1 pre-mRNA which leads to hyperexcitability of skeletal muscle.
- CIC-1 is the main chloride channel in skeletal muscle.
- These experiments were in mice.
- This concept that a gain of triplet expansion can lead to negative affects on many different protein RNA molecules is called a trans-dominant effect.
- This "toxic RNA" is called a trans-dominant effect: one in which excess of a product (in this case RNA) gives it a gain-of-negative-function.
- This is the first well-documented example of this pathogenic mechanism in humans.
- Note that mouse models of myotonic dystrophy are best produced through repeat expansion and are not representative of human disease with simple knockouts.
- There is a second gene that can have a similar "trans-dominant effect": znf9 = dm2
- Expansions in ZNF9 cause myotonic dystrophy type 2 (DM2).
- The repeat expansion in ZNF9 (DM2) is "CCUG" (a quartet repeat) in the first intron.
- ZNF9 expansions generate only a small percentage of myotonic distrophy cases.
- ZNF9 mRNA accumulation interrupts proper RNA processing of other genes.
[edit] Phenotypic information
- Progressive muscle weakness and wasting
- Begins in the face then generalized
- Myotonia: cannot relax after contraction
- From defects in CIC-1 (chloride channel) splicing
- Early cataracts
- Cardiac involvement: conduction defects
- Perhaps from cardiac troponin T splicing defects?
- Endocrine issues: insulin resistance
- Insulin receptor splicing issues
- Reproductive defects: gonadal failure
