Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion

Abstract

The TOR1A and THAP1 genes were screened for mutations in a cohort of 21 Brazilian patients with Primary torsion dystonia (PTD). We identified a de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patient with early onset generalized dystonia with speech involvement. Mutations in these two known PTD genes, TOR1A and THAP1, are responsible for about 10% of the PTD cases in our Brazilian cohort suggesting genetic heterogeneity and supporting the role of other genes in PTD.

Identification and functional analysis of novel THAP1 mutations

“…About 50 different THAP1 mutations have been reported to date. 2,[6][7][8][9][10][11][12][13][14][15][16][17]22 One-third of the mutations represents missense mutations located in the THAP domain and is thought to interrupt DNA binding. Another one-third of the mutations are considered to disturb the NLS, such as nonsense mutations, small insertions/deletions, or missense mutations within the NLS.…”

“…5 About 50 different THAP1 mutations have been reported to date including missense, nonsense, and frameshift mutations. 2,[6][7][8][9][10][11][12][13][14][15][16][17] In addition to the disease-causing mutations, two variants, c.-237_236delinsTT and c.71+9C4A, in the non-coding region of THAP1 may be associated with dystonia. 9,13 DYT6 typically manifests as early-onset generalized or segmental dystonia, frequently with prominent laryngeal involvement and a rostrocaudal evolution of symptoms.…”

Study of the genetic basis of dystonia in Serbian population

“…Velike delecije i insercije do sad nisu opisane. U različitim studijama učestalost mutacija se kretala od 0.6 % (Bonetti et al, 2009) do 4.7% (De Carvalho Aguiar et al, 2010). Podaci o učestalosti DYT6 mutacija se razlikuju među studijama pre svega zbog primenjenih različitih kriterijuma za uključivanje bolesnika u studiju.…”

“…U literaturi do sada nije pokazano postojanje konzistentne korelacije između genotipa i fenotipa kod bolesnika sa DYT6 mutacijom (Fuchs et al, 2009;Bressman et al, 2009;Djarmati et al, 2009;Bonetti et al, 2009;Paisan-Ruiz et al, 2009;Houlden et al, 2010;De Carvalho Aguiar et al, 2010;Clot et al, 2010;Xiao et al, 2010;Zittel et al, 2010;Groen et al, 2010;Söhn et al, 2010;Cheng et al, 2010;Jech et al, 2011;Schneider et al, 2011), pa tako pacijenti koji nose istu mutaciju mogu da se razlikuju u godinama početka bolesti i/ili anatomskoj distribuciji simptoma. Godine pojave prvih simptoma kod bolesnika opisanih u ovoj studiji koji su imali promene u kodirajućim regionima THAP1 sekvence su bile između 7 i 36 godina (srednja vrednost: 14,8 godina).…”

“…Prema dostupnim podacima, rani početak simptoma kod DYT6 bolesnika je izgleda povezan sa mutacijama u N-terminalnom THAP domenu i C-terminalnoj NLS sekvenci, dok je kasni početak u vezi sa mutacijama u C-terminalnom domenu, izuzev NLS sekvence (Fuchs et al, 2009;Bressman et al, 2009;Djarmati et al, 2009;Bonetti et al, 2009;Paisan-Ruiz et al, 2009;Houlden et al, 2010;De Carvalho Aguiar et al, 2010;Clot et al, 2010;Xiao et al, 2010;Zittel et al, 2010;Groen et al, 2010;Sohn et al, 2010;Cheng et al, 2010;Jech et al, 2011;Schneider et al, 2011). Međutim, u prilog nepostojanja jasne genotip-fenotip korelacije, u ovoj studiji je detektovana mutacija u THAP domenu kod bolesnika sa kasnim početkom (Bolesnik 3; Tabela 18), kao i mutacija u C-terminalnom domenu van NLS sekvence kod pacijenta sa ranim početkom bolesti (Bolesnik 5; Tabela 18).…”