Background: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants. Results: Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5′UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM-001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5′UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition. Conclusions: Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.
CITATION STYLE
Monies, D., Al-Shaar, H. A., Goljan, E. A., Al-Younes, B., Al-Breacan, M. M. A., Al-Saif, M. M., … Bohlega, S. (2017). Identification of a novel genetic locus underlying tremor and dystonia. Human Genomics, 11(1). https://doi.org/10.1186/s40246-017-0123-5
Mendeley helps you to discover research relevant for your work.