Identification of a novel genetic locus underlying tremor and dystonia


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. 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. Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.

DOI: 10.1186/s40246-017-0123-5

Cite this paper

@inproceedings{Monies2017IdentificationOA, title={Identification of a novel genetic locus underlying tremor and dystonia}, author={Dorota Monies and Hussam Abou Al-Shaar and Ewa Goljan and Banan Al-Younes and Muna Monther Abdullah Al-Breacan and Maher Mohammed Al-Saif and Salma Majid Wakil and Brian Francis Meyer and Khalid S. A. Khabar and Saeed A. Bohlega}, booktitle={Human Genomics}, year={2017} }