⁇ i>PRPF40B ⁇ /i> geninde homozigot bir sezaryen varyantı olan p.Ser166Leu, esansiyel sarsıntılı bir Türk ailesinde homozigot bir 7.7 Mb bölgesindedir.

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IntroductionWe 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.MethodsThe 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.ResultsA 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.DiscussionThe 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.

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