Bethlem myopathy is a rare form of congenital muscular dystrophy that is caused by mutations in the COL6A1COL6A2or COL6A3 genes. These genes encode for three peptides that make up type 6 collagen.

The most common symptoms of the disease are progressive muscle weakness and joint stiffness (contractures) in the fingers, wrists, elbows, and ankles.

Bethlem myopathy is primarily an autosomal dominant disease, which is caused by a mutation in one copy of the COL6A1, COL6A2, or COL6A3 genes. However, there have been a few reported autosomal recessive cases, in which both copies of the genes were mutated.

Collagen type 6 and Bethlem myopathy

Collagen type 6 is part of the extracellular matrix that provides structural and biochemical support to the surrounding muscle cells and connective tissue. The extracellular matrix is a three-dimensional network made up of compounds called proteoglycans, water, minerals, and fibrous proteins. It is essential for cell stability, intercellular connectivity, and growth.

Three peptides, which are encoded by the Col6A1, Col6A2, and Col6A3 genes, assemble to form the monomeric collagen type 6. The collagen type 6 further bonds to form dimers and tetramers, more complex polymers.

Collagen type 6 plays a significant role in linking the extracellular matrix to the surrounding cells. Faulty or decreased amounts of collagen type 6 destabilize the extracellular matrix, causing detachment from the surrounding muscle cell. That affects its stability and that of its connective tissues, leading to progressive muscle weakness, contractures, and other symptoms characteristic of Bethlem myopathy.

Types of mutations in Bethlem myopathy

Mutations in any of the Col6A1, Col6A2, and Col6A3 genes can lead to the formation of abnormal or reduced amounts of collagen type 6. Several types of mutations have been reported in Bethlem myopathy patients. These are described below.

Single amino acid substitutions

These are mutations that cause single amino acid changes in the Col6A1, Col6A2, or Col6A3 peptides. Amino acids are the building blocks of proteins. When these changes occur in the interaction domain of the Col6A1, Col6A2, and Col6A3 peptides, they disrupt the assembly of a stable collagen type 6 protein, thereby decreasing its levels in the extracellular matrix.

Splice site mutations

Genes are made of regions called exons and introns. Exons are protein-coding sequences, while introns do not code for protein. They have to be removed, or spliced out from the messenger RNA molecule before it is translated into protein. The sequence at the junction of each exon and intron is critical for this splicing process, and is called the splice site. Mutations in the splice site can cause aberrant splicing. This can result in a messenger RNA molecule that contains the wrong code for the protein or a premature termination signal.

For example, a mutation in the splice site that causes the “skipping” of COL6A1 exon 14 during splicing generates an 18 amino acid deletion in the interaction domain of the Col6A1 protein. This disrupts its assembly with the COL6A2 and COL6A3 peptides. Other splice site mutations can cause small in-frame deletions or insertions within the domains immediately adjacent to the interacting domains of COL6A1 and COL6A2 that affect the assembly of collagen type 6 protein.

Nonsense mutations

Nonsense mutations are single nucleotide changes that introduce a premature termination signal to the messenger RNA. For example, a nonsense mutation in the COL6A1 results in a single base deletion from the mRNA sequence, causing a premature stop codon. The resulting mutant mRNA is unstable and is degraded. This causes Bethlem myopathy because the decreased amounts of COL6A1 affect the assembly and levels of collagen type 6 in the extracellular matrix.

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