MRM2 variants in families with complex dystonic syndromes: evidence for phenotypic heterogeneity

Dystonia involves repetitive movements and muscle contractions leading to abnormal postures. We investigated patients in two families, DYAF11 and M, exhibiting dystonic or involuntary movement disorders.

Clinical investigations were performed for all patients. Genetic analyses included genome-wide linkage analysis and exome sequencing followed by Sanger sequencing validation. MRM2-specific transcripts were analysed from participants' blood samples in Family DYAF11 after cloning of gene-specific cDNA.

Four affected siblings in Family DYAF11 had progressive dystonic features. Two patients in Family M exhibited a neurodevelopmental disorder accompanied by involuntary movements. In Family DYAF11, linkage was detected to the telomere at chromosome 7p22.3, spanning <2 Mb. Exome sequencing identified a donor splice-site variant, c.8+1G>T in MRM2, which segregated with the phenotype, corresponding to the linkage data since all affected individuals were homozygous while the obligate unaffected carriers were heterozygous for the variant. In the MRM2 c.8+1G>T allele, an aberrant alternative acceptor splice-site located within exon 2 was used in a subset of the transcripts, creating a frameshift in the open reading frame. Exome sequencing in Family M revealed a rare missense variant c.242C>T, p.(Ala81Val), which affected a conserved amino acid.

Our results expand the clinical and allelic spectrum of MRM2 variants. Previously, these descriptions were based on observations in a single patient, diagnosed with mitochondrial DNA depletion syndrome 17, in whom movement disorder was accompanied by recurrent strokes and epilepsy. We also demonstrate a subset of correctly spliced tt-ag MRM2 transcripts, raising the possibility to develop treatment by understanding the disease mechanism.