Resolution of a mispaired secondary structure intermediate could account for a novel micro-insertion/deletion (387
M A Martín1, J C Rubio, A García
1Centro de Investigación, Hospital 12 de Octubre, Madrid, Spain.
Abstract:
We report two siblings with McArdle's disease who are both compound heterozygotes for two non-identical frameshift mutations in the PYGM gene; a previously reported 753 delA in exon 18 and a novel 387 insA/del 8 bp in exon 10. The novel mutation is predicted to result in premature termination of translation 33 amino acids downstream of the site of mutation, potentially encoding a severely truncated protein of 419 amino acids instead of 841 amino acids. The complete lack of myophosphorylase activity observed in muscle derived from one sibling suggests that this mutation has deleterious functional consequences. The underlying mechanism of mutagenesis may have been slipped mispairing mediated by the formation of a Moebius loop-like secondary intermediate.
Insights
Two siblings with McArdle's disease were found to have compound heterozygous frameshift mutations in the PYGM gene. A novel mutation suggests severe consequences for myophosphorylase activity in this glycogen storage disease.
Area of Science:
- Genetics
- Biochemistry
- Rare diseases
Background:
- McArdle's disease is a rare genetic disorder affecting glycogen metabolism in muscles.
- It is caused by mutations in the PYGM gene, which encodes myophosphorylase.
Observation:
- Two siblings with McArdle's disease presented with compound heterozygous mutations in the PYGM gene.
- One mutation was previously identified (753 delA in exon 18), and a novel mutation (387 insA/del 8 bp in exon 10) was discovered.
Findings:
- The novel PYGM mutation is predicted to cause premature protein termination, resulting in a significantly truncated myophosphorylase (419 aa instead of 841 aa).
- Muscle tissue from one sibling showed a complete absence of myophosphorylase activity, indicating severe functional impairment.
Implications:
- The novel mutation likely has deleterious functional consequences, contributing to the pathophysiology of McArdle's disease.
- Slipped mispairing, potentially involving a Moebius loop intermediate, is proposed as the mechanism for this novel mutation.
- Understanding these specific mutations aids in diagnosing and potentially treating this glycogen storage disease.
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