Genetics & Molecular Biology
Novel KMT2B Mutation Linked to Atypical Dystonia
Original Authors: Iravani, Taghvaei, Sefid, Eslamiyeh
KMT2B-related dystonia is a recognized childhood-onset movement disorder characterized by involuntary muscle contractions. This study aimed to investigate a previously undescribed KMT2B gene variant using whole exome sequencing (WES) and detailed bioinformatics analysis. The ultimate goal was to expand the known clinical spectrum of KMT2B-related dystonia by characterizing an atypical dystonic pattern observed in a specific patient.
The research began with a comprehensive clinical evaluation by a pediatric neurologist of a 13-year-old girl. She presented with an unusual combination of left leg and right-hand spasms, termed cross-dystonia, which had progressively led to difficulties in gait and writing over a two-year period. Her evaluation included brain magnetic resonance imaging and detailed neuro-metabolic testing. Subsequently, her genomic DNA underwent WES, and the newly identified genetic variant was validated through Sanger sequencing, complemented by trio analysis within her family. To further understand the variant's impact, various in silico prediction tools, including SMART, PROSITE, CDD, COACH, and COFACTOR, were employed for a thorough analysis of its structural and functional characteristics.
Molecular investigations through WES analysis revealed a novel pathogenic variant: a heterozygous G→T nonsense mutation at position 1363 in exon 3 of the KMT2B gene (NM_014727.3, c.1363G > T). This mutation is predicted to cause a premature stop codon (NP_055542: p.E455X), which would result in a truncated protein. Bioinformatic analysis using the SEG program indicated that this mutation was located within a low compositional complexity region of the protein, specifically spanning residues 392-463. Predictions from computational methods like SVM, neural networks, and sequence information showed changes in energy values and the sign of energy change, indicating decreased stability in the mutated protein structure.
As lead author Iravani notes in the paper, "This newly identified KMT2B mutation with an unusual clinical phenotype highlighted its regulatory role and underscored the connection between protein structure, function, and disease manifestation." This study thus contributes valuable insights into the genetic underpinnings and phenotypic variability of KMT2B-related dystonia.