Description

A rare form of congenital myopathy known as dominant Centro Nuclear Myopathy (CNM) has a wide range of clinical manifestations, ranging from severe neonatal to milder adult forms. Due to heterozygous mutations in the DNM2 gene, which encodes Dynamin 2, there is no treatment for this disease. Hereditary spastic paraplegia and rare forms of Charcot-Marie-Tooth disease are both caused by dominant DNM2 mutations, and detrimental DNM2 overexpression has been observed in a number of diseases. In a mouse model and patient-derived cells, both expressing the most common DNM2 mutation in CNM, the proof of concept for therapy by allele-specific RNA interference, which aims to silence the mutated mRNA without affecting the normal allele, was previously achieved. We have developed allele-specific siRNAs against two non-pathogenic Single-Nucleotide Polymorphisms (SNPs) that are frequently heterozygous in the population so that we can have versatile small interfering RNAs (siRNAs) that can be used regardless of the mutation. Additionally, p-specific allele-specific siRNAs they discovered the S619L DNM2 mutation, which is frequently linked to severe neonatal cases. A number of defects in patient-derived cell lines have been shown to benefit from these new siRNAs. These novel molecules make it possible to use a small number of siRNAs to target the vast majority of patients with DNM2 overexpression or mutations.

Centronuclear myopathy is a rare congenital myopathy with a wide range of clinical manifestations, ranging from severe neonatal to mild adult forms. The classic late-childhood or adult-onset form causes delayed motor milestones and diffuse skeletal muscle weakness primarily affecting the facial and limb muscles, whereas the severe neonatal form typically causes generalized weakness, hypotonia, and facial weakness in children. AD-CNM is caused by mutations in the DNM2 gene, Hereditary Spastic Paraplegia (HSP), and a deleterious DNM2 overexpression in a number of cancers and the X-linked recessive CNM13 point to a significant role for DNM2 in human diseases. As a mechanochemical scaffolding molecule, DNM2 oligomerizes and deforms biological membranes, resulting in the formation and release of vesicles from the plasma membrane and intracellular membrane compartments. It is a member of the superfamily of large GTPases. More than 30 DNM2 mutations have been found in AD-CNM patients, and when tested, the mutant protein is normally expressed. Mutations are thought to be responsible for a gain-of-function and/or a dominant-negative effect through increased GTPase activity and the formation of abnormal stable DNM2 oligomers. Additionally, patients' data and the absence of a phenotype in heterozygous (HTZ) knockout mice expressing 50% DNM.

In order to find the DNM2 SNPs with the highest human heterozygosity frequency, we conducted an in silico analysis. A frequency of the second most common allele in the general population between 0.1 and 0.5. Two SNPs were found using these criteria. The first SNP was a T/C variation that was found to be a synonymous variant of the DNM2 protein's alanine. The allele frequencies for SNP1 were determined to be 0.688 for the allele T and 0.321 for the allele C, resulting in a theoretical HTZ frequency of 0.43. SNP1 heterozygosity was found in 42.3% of 52 CNM patients by PCR and Sanger sequencing, which were in agreement. The second SNP was an A/T variant on allele frequencies for SNP2 were determined to be 0.824 for allele A and 0.176 for allele T. This yielded a theoretical HTZ frequency of 0.29, and 23% of patients in our cohort had SNP2 heterozygosity. SNPs 1 and 2 were not associated with any clinical sign.

Thanks & Regards
Jackson
Journal coordinator
Journal of Neoplasm