A homozygous missense variant, p.Ser166Leu in the PRPF40B gene, in a 7.7 Mb region of homozygosity in a consanguineous Turkish family with essential tremor

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ONAT O. E., Sonti S., Robakis D., Tekinay A. B., Akbostanci C., DURMAZ ÇELİK F. N., ...Daha Fazla

Frontiers in Neurology, cilt.17, 2026 (SCI-Expanded, Scopus)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 17
  • Basım Tarihi: 2026
  • Doi Numarası: 10.3389/fneur.2026.1796664
  • Dergi Adı: Frontiers in Neurology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, Psycinfo, Directory of Open Access Journals
  • Anahtar Kelimeler: consanguinity, essential tremor, neurological disorder, nuclear speckle protein, Parkinson’s disease, PRPF40B, tremor, Turkish
  • Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
  • Ankara Üniversitesi Adresli: Evet

Özet

Introduction – We leveraged consanguinity and population endogamy in a large four generation Turkish family with ET. Examination of clinical features and genetic analysis identified a homozygous PRPF40B missense variant, in a large region of homozygosity, segregating with ET in the family. Methods – The ET family is of Turkish origin. The proband and relatives were evaluated at Ankara University Medical School and Bilkent University (Ankara, Turkey). A second evaluation of the clinical and videotape data was performed at Yale University. A total of 6 individuals from the family were clinically assessed. Whole genome sequencing and autozygosity mapping was performed in affected and unaffected family members. Transient transfection of HEK293T cells was performed to assess pathogenicity of the PRPF40B missense variant. Results – A total of 4 family members were diagnosed with ET; two individuals also had a diagnosis of Parkinson’s Disease (PD). We identified a missense variant in PRPF40B, p.Ser166Leu, located within a 7.7 Mb region of homozygosity (ROH) (Chr12: 46595701–54, 330, 441), which was observed in all analyzed affected family members. Unlike wildtype PRPF40B which localizes to nuclear speckles in the nuclear compartment, when mutant PRPF40B was expressed in HEK293T cells we observed enrichment and localization to the nuclear membrane. Discussion – The PRPF40B p.Ser166Leu variant is located within a conserved region of the WW protein domain. In Silico pathogenicity and functional studies predict that the missense variant alters the function of PRPF40B. PRPF40B has previously been implicated in the pathogenesis of neurological disorders, including Huntington’s disease and Rett syndrome.