Movement Disorder Associated With Mutation That Impairs DNA Binding

Jacquelyn K Beals, PhD

February 27, 2009

February 27, 2009 — Researchers have identified a mutation in THAP1 that cosegregates with primary torsion dystonia in affected members of 3 Amish-Mennonite families, according to an article published in the March issue of Nature Genetics. An unrelated THAP1mutation was found in affected members of a family with no Amish-Mennonite heritage, suggesting that THAP1 plays a role in dystonia across ethnic groups. THAP1is the second gene to be specifically associated with any of the 15 or more forms of dystonia.

Primary torsion dystonia is a group of movement disorders in which dystonia is the only neurologic characteristic. Dystonias differ in their genetic causes, but the majority show autosomal dominant inheritance. Dystonia 6 (DYT6), occurring in Amish-Mennonite families, begins in adolescence or early adulthood. Symptoms include twisting motions and abnormal postures of the limbs, head, and neck. Despite its dominant inheritance pattern, the phenotype is penetrant in only 60% of mutation carriers.

The 2 THAP1 mutations were identified by Laurie J. Ozelius, PhD, from the Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, and colleagues at several New York medical institutions. The first dystonia gene identified was associated with DYT1, but genes for other dystonias have been localized only to a chromosomal region.

The DYT6 gene was already known to lie on human chromosome 8, in a region containing approximately 120 genes. The present study sequenced these genes in patients with DYT6 and identified an insertion of 5 base pairs followed by a deletion of 3 base pairs within THAP1. The net gain of 2 base pairs causes a "frame shift" — the triplet codes are read from a different starting point, encoding the wrong amino acids and causing early termination of the protein.

The investigators found this insertion-deletion mutation in 23 patients with DYT6 dystonia from 3 Amish-Mennonite families, but not in the chromosomes of Amish-Mennonite control individuals (n = 280). The study screened 2 additional families with possible Amish-Mennonite ancestry and similar clinical histories. The first family demonstrated the same insertion-deletion mutation of THAP1 in affected individuals.

The second family did not demonstrate this mutation, and genealogical study found no Amish-Mennonite ancestors. Instead, THAP1 sequencing identified a single base substitution (cytosine for thymine) that incorporated leucine rather than phenylalanine in the gene product. This mutation was present in 4 family members with dystonia but not in control individuals (n = 514). Quoted in a Mount Sinai press release, Dr. Ozelius said the second mutation suggests that "THAP1 mutations may cause dystonia in other ancestry groups" besides the Amish-Mennonites.

Recent determinations of THAP1 structure and function suggest that the mutation in Amish-Mennonite families may produce a protein that lacks DNA-binding activity. The present study also showed that the altered protein product of THAP1 with base substitution has lower binding affinity for its target DNA. The authors speculate that loss of DNA binding impairs the transcription regulation of target genes in individuals with DYT6 dystonia.

"Identification and characterization of downstream targets of THAP1 should provide a basis for investigating the pathophysiology and devising novel treatments for this poorly understood and disabling disease," the authors conclude.

Nat Genet. 2009;41(3):286–288.

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