Direct interaction between causative genes of DYT1 and DYT6 primary dystonia

Abstract

Primary dystonia is a movement disorder characterized by sustained muscle contractions and in which dystonia is the only or predominant clinical feature. TOR1A (DYT1) and the transcription factor THAP1 (DYT6) are the only genes identified thus far for primary dystonia. Using electromobility shift assays and chromatin immunoprecipitation (ChIP)-qPCR, we demonstrate a physical interaction between THAP1 and the TOR1A promoter that is abolished by pathophysiologic mutations. Our findings provide the first evidence that causative genes for primary dystonia intersect in a common pathway and raise the possibility of developing novel therapies targeting this pathway.

DYT6 Dystonia: A Neuropathological Study

“…Mutations in the THAP1 domain are thought to interrupt DNA binding, causing transcriptional dysregulation of THAP1 target genes [1]. A functional study in a THAP1 case with a frameshift mutation in the nuclear localizing signal region of THAP1 demonstrated an impaired nuclear import of mutant THAP1 in vitro [18]; THAP1 is reported to interact with the promoters of TOR1A , mutations of which cause DYT1 dystonia [19], TAF1 , implicated in DYT3 dystonia [20], and recently THAP1 has been reported to autoregulate its own expression [21]. Hence, studies of biochemical and cellular mechanisms may provide a link to abnormal motor control in DYT6 dystonia.…”

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

“…Two reports demonstrate that THAP1 can bind the TOR1A promoter [100,101]; both find that DYT6 mutations impair this association. One of these studies [100] demonstrated that THAP1 could enhance the expression of a luciferase reporter linked to the TOR1A promoter, but no differences in torsinA mRNA or protein were observed in fibroblasts derived from DYT6 dystonia subjects.…”

Study of the genetic basis of dystonia in Serbian population

“…Najnovije studije ukazuju na funkcionalnu povezanost THAP1 i TOR1A proteina, a time i na zajedničke molekularne osnove DYT6 i DYT1 distonije. In vitro studije su pokazale da se THAP1 vezuje za promotorski region TOR1A gena i reguliše njegovu ekspresiju (Kaiser et al, 2010;Gavarini et al, 2010). Pokazano je da wt THAP1 snižava ekspresiju TOR1A, dok mutirani THAP1 smanjuje ovu represiju nad TOR1A.…”

“…Međutim, u kultivisanim fibroblastima u kojima je THAP1 utišan pomoću RNK interferencije, ili u fibroblastima koji su nosili heterozigotnu THAP1 mutaciju, nije bilo značajnih promena nivoa ekspresije TOR1A (Kaiser et al, 2010). Slično, u limfoblastoidnim ćelijskim linijama bolesnika sa THAP1 mutacijama nije uočena promena u nivou TOR1A ekspresije (Gavarini et al, 2010). Moguće objašnjenje bi bilo da je THAP1-TOR1A interakcija patofiziološki relevantna samo u CNS-u ili čak samo u određenim podtipovima neurona.…”

“…U prilog patogenosti ove mutacije ide i podatak da je u studiji Bressman i saradnika (2009), kod porodice sa dva obolela člana, opisana mutacija koja pogađa istu aminokiselinsku reziduu (p.Ser21Thr). Takođe, pokazano je da p.Ser21Thr mutacija u THAP domenu dovodi do narušavanja THAP1/TOR1A interakcije in vivo (Gavarini et al, 2010). Na osnovu navedenih podataka može se zaključiti da je p.Ser21Cys promena verovatno patogena.…”