Genetics of Myotubular Myopathy
X-linked Myotubular Myopathy (XLMTM)
The X-linked form is of Myotubular Myopathy (XLMTM) caused by a mutation in the MTM1 gene. MTM1 is needed to produce myotublarin an enzyme thought to be involved in the development and maintenance of muscle cells.
MTM1 gene mutations are thought to disrupt myotubularin's normal role in muscle cell development and maintenance. This then causes muscle weakness and other signs and symptoms of X-linked Myotubular Myopathy (XLMTM). This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. As with other X-linked recessive conditions, in males (who have only one X chromosome, plus one Y chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), the mutation in one X chromosome is compensated for by their other X chromosome - a mutation would have to be present in both copies of the gene to cause the disorder. Because it is highly unlikely that females will have two altered copies of this gene, it is only males that are affected by X-linked recessive disorders. A characteristic of X-linked inheritance is that affected fathers cannot pass X-linked traits to their sons, but all their daughters will be carriers of the condition.
In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder. In rare cases, however, carrier females have experienced some muscle weakness associated with X-linked Myotubular Myopathy.
This is often associated with a mechanism called "skewed X-inactivation": As females don't need both of their X chromosomes, in any given cell half of all X chromosomes are switched off, in a process called "X inactivation" (or "lyonization"). This process usually occurs randomly but very rarely, one copy of the X chromosome may be active much more than the other ("skewed X-inctivation"); if this copy happens to carry a gene fault, females may develop symptoms of conditions that usually only affect males.
Autosomal Centronuclear Myopathy (dominant and recessive)
The majority of described Centronuclear Myopathy cases have been attributed to mutations in the DNM2 and BIN1 genes, and more recently mutations in the RYR1 gene. More recently, mutations in the TTN gene have also been associated with centronuclear Myopathy, but the frequency of this form is currently not certain. However some cases still remain unknown.
Mutations in the DNM2 gene causing CNM are usually associated with dominant inheritance, mutations in the RYR1 gene are usually associated with recessive inheritance, whereas mutations in the BIN1 gene have been associated with both dominant and recessive inheritance.
The DNM2 gene provides instructions for making a protein called dynamin 2 and the BIN1 gene encodes a protein called amphiphysin 2. Both proteins are involved in trafficking of cell membranes and do interact with each other. The RYR1 gene encodes the skeletal muscle ryanodine receptor, which is involved in intramuscular calcium release and excitation-contraction coupling, the process whereby the nerve impulse from the brain is translated into muscle contraction. The TTN gene encodes Titin, a giant protein that is fundamental in giving muscle its structure.
Normally, the nucleus is found at the edges of muscle cells, however, in people with centronuclear Myopathy, the nucleus is located in the centre of these cells. It is not well understood how mutations in the DNM2, BIN1, RYR1 or TTN genes lead to muscle weakness and the other specific features of centronuclear Myopathy, however, there is likely to be more than one mechanism in place, including disturbances of muscle membrane trafficking, muscle fibre integrity and/or excitation-contraction coupling.
