SORL1 mutation in a Greek family with Parkinson's disease and dementia

Abstract

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson’s disease and Parkinson’s disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.

Evaluation of SORL1 in Lewy Body Dementia Identifies No Significant Associations

“…Furthermore, a recent report examining SORL1 mutations in a large Greek family with Parkinson's disease, Parkinson's disease dementia, and mixed dementia reported a rare missense variant (p.G379W) segregating with disease. 6 We observed the same mutation in one patient of Greek ancestry with LBD. From our data, we cannot conclude that this mutation is disease-causing or simply a variant present in the Greek population.…”

“…We observed eight missense mutations that have been previously described in patients with mixed dementias. [4][5][6] However, these mutations were either found in cases and controls or were more frequent in controls. None of these variants were nominally associated with disease (Table 1).…”

“…4 Interestingly, several studies have also found rare SORL1 mutations in patients with Alzheimer's disease with concomitant LBD, suggesting that SORL1 may be a pleiotropic risk gene. [4][5][6] Here, we assessed the possible association of SORL1 variants with risk for LBD.…”

Whole Exome Sequencing Study in Isolated South-Eastern Moravia (Czechia) Population Indicates Heterogenous Genetic Background for Parkinsonism Development

“…It would prepare a field for finding of novel causal or risk genes and variants. NOTCH4 ( Yemni et al, 2019 ), TNK2, TNR ( Farlow et al, 2016 ), NUS1 ( Guo et al, 2018 ), and SORL1 ( Xiromerisiou et al, 2021 ) belong to the potential candidate genes recently identified by WES. Combination of WES data and linkage analysis can be used for identification of novel candidate genes in many diseases ( Gazal et al, 2016 ; Toma et al, 2020 ).…”

Endophenotypic effects of the SORL1 variant rs2298813 on regional brain volume in patients with late-onset Alzheimer’s disease

“…Targeted single-nucleotide polymorphism (SNP) analyses and genome-wide association studies have validated the association not only in populations of Caucasian origin but also in Asian populations (Reitz et al, 2011;Lambert et al, 2013;Miyashita et al, 2013). A number of studies have shown significant associations between specific SORL1 polymorphisms and various phenotypes in AD patients, including lower Aβ levels in cerebrospinal fluid (Alexopoulos et al, 2011) and serum (Chou et al, 2016), increased tau protein in cerebrospinal fluid (Louwersheimer et al, 2015), hippocampal atrophy (Cuenco et al, 2008;Louwersheimer et al, 2015;Xiromerisiou et al, 2021), white matter hyperintensity (Cuenco et al, 2008), frontal symptoms (Huang et al, 2020), rate of cognitive decline (Hsieh et al, 2021), and Parkinsonian features (Cuccaro et al, 2016;Xiromerisiou et al, 2021).…”