Myotonic Dystrophy

From Iusmgenetics

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

[edit] Diagnosis

[edit] Treatment

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers

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