Team identifies genetic defect that may cause rare movement disorder

February 22, 2018, Massachusetts General Hospital
Credit: CC0 Public Domain

A Massachusetts General Hospital (MGH)-led research team has found that a defect in transcription of the TAF1 gene may be the cause of X-linked dystonia parkinsonism (XDP), a rare and severe neurodegenerative disease. The study, published in the February 22 issue of Cell, is a collaboration between the laboratories of Michael Talkowski, PhD, and Cristopher Bragg, PhD, both of the MGH Department of Neurology and the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP).

"Even though the first clinical descriptions of this disease were published more than 40 years ago, it has been difficult to determine its cause or what might be done to treat it," says Talkowski, who is also a member of the MGH Center for Genomic Medicine. "Perhaps the biggest challenge with XDP has been understanding its genetic basis, and without knowing the causative gene defect, it has been hard to hypothesize about the underlying disease mechanisms."

Occurring only among individuals with ancestry from the Philippines island of Panay, XDP causes the death of certain within the brain. Symptoms begin around age 40 with dystonia - involuntary muscle contractions that can force the body into abnormal, sometimes twisted positions - and eventually proceed to Parkinson's-like symptoms, such as slowness of movement and a shuffling gait. Patients become progressively more disabled as the disease progresses and often die from complications such as infections or pneumonia.

Prior to this study, it had been reported that all individuals with XDP share seven DNA sequence changes, which cluster within a region of the X-chromosome that includes the TAF1 gene. Bragg explains, "These sequence changes have always appeared to be inherited together; in other words, all reported patients had all seven sequence variants, and none have ever been found in unaffected people. Because of this pattern, it had not been possible to determine which, if any, of these changes may be pathogenic."

To address that question, Talkowski and Bragg worked with CCXDP Director, Nutan Sharma, MD, PhD, to mount the largest genomics study ever performed for XDP, analyzing a total of 792 DNA samples from individuals with XDP and their unaffected relatives, as well as historical samples from studies dating back to the initial descriptions of the disease. The analysis of these samples revealed a far greater genetic diversity among XDP patients than was previously known. While most shared a total of 54 unique sequence changes in a collection of variants known as a haplotype, in some individuals the haplotype had been broken apart due to genetic recombination. By comparing these recombination events, it was possible to narrow the disease-causing genomic segment to a smaller region that contained only the TAF1 gene.

To further pinpoint any altered functions associated with these variants, the Bragg laboratory reprogramed skin cells from patients with XDP and their healthy relatives back into stem cells, which differentiated into and then mature neurons. Talkowski's team used RNA sequencing to characterize TAF1 expression patterns and found a defect in how the DNA sequence is transcribed into RNA in neural cells from XDP patients. In those cells, a portion of the TAF1 RNA appeared to terminate prematurely, which reduced expression of the full-length RNA. The truncated TAF1 RNA ended close to a known XDP-specific sequence variants - a large DNA insertion known as a retrotransposon. To determine whether the retrotransposon caused the transcriptional defect, the Bragg lab used genome editing tools to remove the sequence, which restored RNA transcription and normalized TAF1 expression.

In a separate study published last December in PNAS, Bragg and colleague, Laurie Ozelius, PhD, also of MGH Neurology, had analyzed the sequence of the retrotransposon in patients with XDP and found that it contained a segment of repetitive DNA that was longer in patients who developed symptoms at an earlier age and shorter in those whose symptoms appeared later. Bragg says, "The combined results of these two studies provide the strongest evidence to date that this retrotransposon is the most likely cause of XDP."

Talkowski adds, "We cannot say definitively that this mechanism is the sole cause of XDP. There is still much work to do. However, it is a major step forward in understanding the defects that occur in patients' cells, and the integrated genomic approaches we have used might be applicable to other unsolved disorders. This finding in XDP is particularly exciting given the tremendous advances that have occurred in recent years with RNA-based therapeutics. The possibility that XDP may result from defective transcription means there may be ways to treat it, and that is certainly cause for hope."

Explore further: Team identifies DNA element that may cause rare movement disorder

More information: Cell (2018). DOI: 10.1016/j.cell.2018.02.011

Related Stories

Team identifies DNA element that may cause rare movement disorder

December 11, 2017
A team of Massachusetts General Hospital (MGH) researchers has identified a specific genetic change that may be the cause of a rare but severe neurological disorder called X-linked dystonia parkinsonism (XDP). Occurring only ...

Team identifies gene mutations behind lack of a nose

January 10, 2017
Researchers from Massachusetts General Hospital (MGH) led a large, international research team that has identified gene mutations associated with a rare congenital condition involving the absence of a nose and often accompanied ...

Researchers home in on mutation profiles of clear cell endometrial cancer

May 9, 2017
In the largest genomics study of clear cell endometrial cancer (CCEC) tumors to date, National Human Genome Research Institute (NHGRI) researchers and their collaborators have identified mutations in the TAF1 gene. They've ...

Deep brain stimulation for the treatment of movement disorders

December 27, 2017
For the first time, researchers from Charité have shown that in patients with a type of movement disorder known as dystonia, a particular pattern of brain activity is linked to both the severity of symptoms and the clinical ...

Discovery of X-linked intellectual disability syndrome is aided by web tools

December 3, 2015
It's a genetic detective story with a distinct 21st-century flavor. A geneticist from Cold Spring Harbor Laboratory (CSHL) in the United States has used powerful internet and social media tools to find doctors and researchers ...

Scientists repair gene defect in stem cells from patients with rare immunodeficiency

January 11, 2017
Scientists have developed a new approach to repair a defective gene in blood-forming stem cells from patients with a rare genetic immunodeficiency disorder called X-linked chronic granulomatous disease (X-CGD). After transplant ...

Recommended for you

Scientists identify method to study resilience to pain

December 14, 2018
Scientists at the Yale School of Medicine and Veterans Affairs Connecticut Healthcare System have successfully demonstrated that it is possible to pinpoint genes that contribute to inter-individual differences in pain.

CRISPR joins battle of the bulge, fights obesity without edits to genome

December 13, 2018
A weighty new study shows that CRISPR therapies can cut fat without cutting DNA. In a paper published Dec. 13, 2018, in the journal Science, UC San Francisco researchers describe how a modified version of CRISPR was used ...

Noncoding mutations contribute to autism risk

December 13, 2018
A whole-genome sequencing study of nearly 2,000 families has implicated mutations in 'promoter regions' of the genome—regions that precede the start of a gene—in autism. The study, which appears in the December 14 issue ...

New method for studying ALS more effectively

December 13, 2018
The neurodegenerative disease ALS causes motor neuron death and paralysis. However, long before the cells die, they lose contact with muscles as their axons atrophy. Researchers at Karolinska Institutet in Sweden have now ...

Paternal grandfather's high access to food may indicate higher mortality risk in grandsons

December 12, 2018
A paternal grandfather's access to food during his childhood is associated with mortality risk, especially cancer mortality, in his grandson, shows a large three-generational study from Stockholm University. The reason might ...

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.