TMEM151A variants associated with paroxysmal kinesigenic dyskinesia

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Transmembrane protein 151A (TMEM151A) is a recently identified gene associated with autosomal dominant paroxysmal kinesigenic dyskinesia (PKD).
• The spectrum of TMEM151A mutations and their clinical impact in PKD require further elucidation, particularly in diverse populations.

Purpose of the Study:

• To expand the clinical and mutation spectrum of PKD by analyzing sporadic and familial cases.
• To clarify the clinical and genetic features of Chinese PKD patients with TMEM151A variants.
• To investigate the pathogenic mechanisms linking TMEM151A mutations to PKD.

Main Methods:

• Whole exome sequencing was performed on 26 sporadic PKD patients and nine familial PKD pedigrees lacking PRRT2 variants.
• Quantitative real-time PCR was used to assess gene expression in a patient with a frameshift TMEM151A mutation.
• A comprehensive review of previously reported TMEM151A variants was conducted.

Main Results:

• Four TMEM151A variants, including a frameshift and two missense mutations, were identified in four unrelated families.
• The frameshift mutation (c.606_607insA) may lead to TMEM151A mRNA decay, suggesting haploinsufficiency as a pathogenic mechanism.
• Patients with TMEM151A variants presented with short-duration dystonic attacks.

Conclusions:

• TMEM151A variants are a significant cause of PKD, expanding the known genetic basis of the disorder.
• This study identifies a novel TMEM151A mutation and provides detailed clinical descriptions of affected individuals.
• The findings contribute to a better understanding of the pathoetiology of PKD associated with TMEM151A mutations.