Myotonic Dystrophy

From Iusmgenetics

Contents 1 Myotonic Dystrophy 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

[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