Screening of the TMEM151A Gene in Patients With Paroxysmal Kinesigenic Dyskinesia and Other Movement Disorders
Ling-Yan Ma1,2, Lin Han3, Meng Niu4
1Department of Neurology, Center for Movement Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Background:
Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent involuntary movements usually triggered by sudden movements. Mutations in the TMEM151A gene were found to be the causative factor of PKD in recent studies. It has also been revealed that loss-of-function is the mechanism by which TMEM151A mutations cause PKD.
Methods:
To investigate the genetic basis of PKD and broaden the clinical spectrum of the TMEM151A mutations, we recruited 181 patients of Chinese origin with movement disorders (MDs), including 39 PRRT2-negative PKD, 3 paroxysmal exercise-induced dyskinesia (PED), 2 paroxysmal non-kinesigenic dyskinesia (PNKD), 127 isolated dystonia, 8 choreas, and 2 myoclonus-dystonia syndromes. Whole-exome sequencing was applied to identify their possible disease-causing mutations. Then, Sanger sequencing was performed for validation and co-segregation analysis. Genetic analysis was also performed on additional family members of patients with TMEM151A mutations. Clinical manifestations of all PKD cases with mutations in TMEM151A reported, so far, were reviewed.
Results:
Two novel variants of the TMEM151A gene (NM_153266.4, NP_694998.1), c.627_643dup (p.A215Gfs*53) and c.627delG (p.L210Wfs*52), were identified in 2 patients with PKD by whole-exome sequencing and further Sanger sequencing. Both variants were inherited by the patients from their respective mothers. No mutation of the TMEM151A gene was found in the other type of movement disorders. In reviewing the clinical presentation of TMEM151A-related PKD, no statistically significant difference in the age of onset, family history, duration of attacks, laterality, and phenotype was found between genders. More male patients received treatment and had a good response. A higher proportion of female patients did not receive any treatment, possibly because they had a milder condition of the disease.
Conclusions:
This study further validated the role of TMEM151A in PKD. Future studies on protein function will be needed to ascertain the pathogenesis of TMEM151A in PKD.
Insights
This study identified two new TMEM151A gene variants causing paroxysmal kinesigenic dyskinesia (PKD). The findings confirm TMEM151A
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder causing involuntary movements triggered by sudden actions.
- Recent studies identified mutations in the TMEM151A gene as a cause of PKD.
- Loss-of-function is the proposed mechanism for TMEM151A mutations in PKD.
Purpose of the Study:
- To investigate the genetic underpinnings of PKD.
- To expand the known clinical spectrum of TMEM151A mutations.
- To identify novel genetic variants associated with movement disorders.
Main Methods:
- Recruited 181 Chinese patients with various movement disorders.
- Employed whole-exome sequencing to detect mutations.
- Utilized Sanger sequencing for variant validation and co-segregation analysis.
Main Results:
- Identified two novel TMEM151A variants (c.627_643dup and c.627delG) in two PKD patients.
- Both variants were maternally inherited.
- No TMEM151A mutations were found in other movement disorder types.
- Clinical presentation analysis revealed no significant gender-based differences in onset, family history, or phenotype, though males showed better treatment response.
Conclusions:
- This research reinforces the role of TMEM151A in the pathogenesis of PKD.
- Further investigation into TMEM151A protein function is necessary to fully understand PKD mechanisms.
More Related Videos
09:34Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
10:41Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia
Published on: September 12, 2020