LGMD2I, like all the LGMDs, is a “monogenic” disease. “mono-” means ONE, and “-genic” means GENE. A monogenic disease is caused by mutation(s) in ONE of our genes.
In “From Gene to Protein” and “Proteins, the Cell’s Workforce”, we saw how some mutations, even if it is the smallest of change in our genes, can have an impact on the sequence of the corresponding proteins.
That is exactly what happens in people affected with LGMD2I. Let’s take the example of the people diagnosed as homozygous for the common mutation c.826C>A.
- Just one of the 1487 nucleotides of the FKRP gene is changed (see “From Gene to Protein”). The nucleotide #826 is changed from a “C “(cytosine) to an “A “(Adenine).
- This single-nucleotide change causes the change of one of the 495 amino acids or building blocks of the FKRP protein. The amino-acid #276 is changed from an L (Leucine) to an I (Isoleucine).
- The FKRP protein is thought to be an enzyme (see “Proteins, the cells’ workforce”) that modifies another protein called alpha-dystroglycan.
- The change of unit #276 from “L” to “I” prevents the protein from folding onto itself correctly. This change decreases the efficiency of FKRP in modifying the alpha-dystroglycan.
- The alpha-dystroglycan is not functional because it is not properly modified by FKRP. It is thought that this leads to a weakened muscle membrane that is less able to withstand the repeated cycle of extension/contraction of a working muscle.