Nowe warianty genetyczne w genie TMEM151A zidentyfikowane u pacjentów z dyskinezyą kinezjogenną przerywaną
Novel Variants in TMEM151A Identified in a Cohort of Patients with Paroxysmal Kinesigenic Dyskinesia
W skrócie
[Preprint - wstępne wyniki] Naukowcy znaleźli trzy nowe mutacje w genie TMEM151A u pacjentów z rzadką chorobą neurologiczną zwaną dyskinezyą kinezjogenną przerywaną (PKD), która powoduje nagłe, niekontrolowane ruchy ciała. Badania genetyczne oraz analizy strukturalne białek sugerują, że wszystkie warianty genetyczne mogą działać w podobny sposób, polegający na osłabieniu funkcji białka, a nie na jego całkowitym utracie. Wyniki potwierdzają, że pacjenci z mutacjami w genie TMEM151A zazwyczaj reagują dobrze na leki blokujące kanały sodowe, a choroba zwykle zaczyna się w wieku dospiewania.
Oryginalny abstract (angielski)
Abstract Methods We recruited 31 sporadic PKD patients and 10 familial pedigrees from the Departments of Neurology at Henan Provincial People’s Hospital between June 2023 and April 2025. Whole-exome sequencing (WES) was performed to identify pathogenic variants, followed by Sanger sequencing for validation and segregation analysis. In silico structural modeling and protein stability analyses were conducted for missense variants. A systematic literature review was performed to further characterize TMEM151A -related PKD. Results Three TMEM151A variants were identified in one sporadic case and two familial pedigrees, including two novel missense variants (c.894G > T [p.Trp298Cys] and c.899T > C [p.Leu300Pro]) and one frameshift variant (c.943dup[p.Val315GlyfsTer31]. Notably, in one pedigree, the variant carrier presented with epilepsy without PKD, indicating phenotypic heterogeneity and incomplete penetrance. Structural analyses suggested that missense variants may impair protein stability by altering hydrogen bonding networks. Combined with 74previously reported cases, TMEM151A -related PKD typically presents with adolescent onset, brief dystonic episodes, and a favorable response to sodium channel blockers. No significant differences in age at onset or remission were observed between truncating and missense variants, suggesting a shared pathogenic mechanism. Conclusions This study expands the mutational spectrum of TMEM151A by identifying three previously unreported variants and further refines the clinical characterization of TMEM151A -associated PKD. Our findings support that mutation type is not a major determinant of clinical phenotype, implicating a potential common mechanism such as haploinsufficiency.