Format

Send to

Choose Destination
Mov Disord. 2016 Apr;31(4):471-7. doi: 10.1002/mds.26600. Epub 2016 Mar 17.

Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High-Throughput Sequencing.

Author information

1
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
2
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom.
3
Dipartimento di Scienze Neurologiche e del Movimento, Università di Verona, Verona, Italy.

Abstract

Dystonia is a genetically heterogenous disease and a prototype disorder where next-generation sequencing has facilitated the identification of new pathogenic genes. This includes the first two genes linked to recessively inherited isolated dystonia, that is, HPCA (hippocalcin) and COL6A3 (collagen VI alpha 3). These genes are proposed to underlie cases of the so-called DYT2-like dystonia, while also reiterating two distinct pathways in dystonia pathogenesis. First, deficiency in HPCA function is thought to alter calcium homeostasis, a mechanism that has previously been forwarded for CACNA1A and ANO3. The novel myoclonus-dystonia genes KCTD17 and CACNA1B also implicate abnormal calcium signaling in dystonia. Second, the phenotype in COL6A3-loss-of-function zebrafish models argues for a neurodevelopmental defect, which has previously been suggested as a possible biological mechanism for THAP1, TOR1A, and TAF1 based on expression data. The newly reported myoclonus-dystonia gene, RELN, plays also a role in the formation of brain structures. Defects in neurodevelopment likewise seem to be a recurrent scheme underpinning mainly complex dystonias, for example those attributable to biallelic mutations in GCH1, TH, SPR, or to heterozygous TUBB4A mutations. To date, it remains unclear whether dystonia is a common phenotypic outcome of diverse underlying disease mechanisms, or whether the different genetic causes converge in a single pathway. Importantly, the relevance of pathways highlighted by novel dystonia genes identified by high-throughput sequencing depends on the confirmation of mutation pathogenicity in subsequent genetic and functional studies. However, independent, careful validation of genetic findings lags behind publications of newly identified genes. We conclude with a discussion on the characteristics of true-positive reports.

KEYWORDS:

calcium homeostasis; disease mechanism; dystonia; neurodevelopment; next-generation sequencing

PMID:
26991507
DOI:
10.1002/mds.26600
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center