Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases

Abstract

An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.

Fig. 1

Genomic structure of human THAP1. (A) UCSC Genome Browser on human GRCh37/hg19 assembly. From top to bottom: (1) localization of THAP1 is shown on an ideogram of Chr8, (2) UCSC and RefSeq genes on reverse strand - exon 1 is to the right of exons 2 and 3], (3) gene boundaries, (4) CpG islands, (5) DNA methylation in GM12878, H1-hESC, K562, HeLA-S3, and HepG2 cells by reduced representation bisulfite sequencing from ENCODE/Hudson Alpha, (6) H3K4me3 ChIP-seq raw signal, (7) MRE-seq CpG score, (8) MeDIP-seq CpG score, and (8) repeating elements by RepeatMasker. (B) Location of intronic and promoter sequence variants. Untranslated regions (UTRs) are shown in gray. Coding regions of Exons 1, 2 and 3, appear red, yellow and green, respectively. The major isoform (NM_018105.2) contains 3 exons and is 2189 nt in length. Aberrant transcripts containing stop codons 5′ to c.213 may be subject to nonsense mediated decay (NMD).

Fig. 2

THAP1 protein. (A) Functional domains of THAP1 and the location of THAP1 coding sequence variants that have been associated with dystonia. THAP, thanatos-associated protein domain. Pro, low complexity proline-rich region. NLS, nuclear localization signal. M1?, c.2delT or c.1A>G. (B) Multiple sequence alignment of THAP1 from human, mouse, rat, chimpanzee, rhesus monkey, dog, cow, opossum, chicken, Xenopus and zebrafish. Color codes: AVFPMILW-red (small+ hydrophobic including aromatic - Y), DE-blue (acidic), RK-magenta (basic), and STYHCNGQ-green (hydroxyl + amine + basic + Q). Symbols: (*) residues in that column are identical in all sequences, (:) conserved substitutions have been observed, and (.) semi-conserved substitutions are observed.

Fig. 3

Pedigrees of three kindreds with THAP1 dystonia. All family members that provided DNA were genotyped: +/+, wild-type; and +/−, heterozygous. Probands are denoted with arrows. Photograph shows cervical dystonia with right rotational torticollis in the p.S21C proband at 12 years of age.