Myotonic Dystrophy
From Iusmgenetics
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[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