FCMD is characterized by severe dystrophy and weakness of skeletal muscles, neuronal issues such as mental retardation and epilepsy, and eye abnormalities. It is reported almost exclusively in Japanese populations and rarely seen in other places in the world.
How faulty fukutin causes FCMD
While the exact function of the fukutin protein is not known, it is thought to be an enzyme that adds sugar molecules to newly synthesized proteins such as alpha-dystroglycan. That process is known as glycosylation. Alpha-dystroglycan is one of two proteins — the other being beta-dystroglycan — that form the dystroglycan protein complex. The dystroglycan protein complex maintains the structure of muscles, and also plays a role in nerve cell development.
Mutations in the FKTN gene reduce the amount of functional fukutin protein in the cells. This causes defective glycosylation of α-dystroglycan, which significantly reduces its function. As a result, the muscle fibers get damaged during muscular activity, causing progressive muscle weakness and atrophy, or degeneration.
Moreover, defective α-dystroglycan causes some neurons to migrate past the surface of the brain into the fluid-filled space that surrounds it. This leads to one of the characteristic features of FCMD, called cobblestone lissencephaly.
FKTN gene mutations and FCMD
Different types of mutations in the FKTN gene can cause FCMD. These mutations disrupt the coding sequence of the gene. The resulting abnormal protein is synthesized with significantly reduced function or gets degraded by the cell.
A missense mutation refers to a change in a single nucleotide, or “DNA letter” in the gene. Such mutations change the code from one particular amino acid — the building blocks of proteins — to another in the protein sequence. Since the amino acid sequence of the protein defines its function, changing the sequence of amino acids can produce a non-functional protein. It also can cause the degradation or breakdown of the abnormal protein.
A nonsense mutation refers to a single nucleotide change in the gene sequence that can introduce a stop signal instead of an amino acid. When this happens, a truncated or shortened protein is made that will not have the complete sequence required for its normal function. As a result, the protein is either degraded or may not be able to perform the required function.
An insertion is when a piece of DNA is inserted in the coding sequence of the gene. It is thought that, during human evolution, a 3,000-letter-long piece of DNA coming from a virus was inserted in the FKTN gene. This is believed to have introduced a premature stop signal in the coding sequence, which caused the loss of a critical portion of the fukutin protein. This mutation is also called a founder mutation, which refers to the original mutation that altered the gene and is found in the majority of the individuals. Such mutations are observed with high frequency in a group that is or was geographically or culturally isolated.
In most cases, people with FCMD have both copies of the FKTN gene altered by the founder mutation. In rare cases, FCMD patients are compound heterozygote, which means that one copy of the FKTN gene carries the founder mutation while the other has a different mutation (missense, nonsense, or a different insertion) that alters the function of the fukutin protein.
Last updated: August 29, 2019
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