New endemic familial parkinsonism in south Moravia, Czech Republic and its genetical background

Abstract

An increased prevalence of familial neurodegenerative parkinsonism or cognitive deterioration was recently found in a small region of southeastern Moravia.The aim of the study was to assess the genetic background of this familial disease.Variants in the ADH1C, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PRKN, DJ-1, PINK1, PLA2G6, SNCA, UCHL1, VPS35 genes were examined in 12 clinically positive probands of the pedigree in which familial atypical neurodegenerative parkinsonism was identified in previous epidemiological studies. Libraries were sequenced by massive parallel sequencing (MPS) on the Personal Genome Machine (PGM; Ion Torrent). Data were analyzed using Torrent Suite and IonReporter software. All variants were then verified and confirmed by Sanger sequencing.We identified 31 rare heterozygous variants: 11 missense variants, 3 synonymous variants, 8 variants in the UTR region, and 9 intronic variants. Six variants (rs1801334, rs33995883, rs35507033, rs781737269, rs779760087, and rs63750072) were evaluated as pathogenic by at least one in-silico predictor.No single “founder” pathogenic variant associated with parkinsonism has been found in any of the probands from researched pedigree. It may rather be assumed that the familial occurrence of this disease is caused by the combined influence of several “small-effect” genetic variants that accumulate in the population with long-lasting inbreeding behavior.

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

“…Variants in a variety of genes have been reported to be associated with PD, including SNCA (encoding α-synuclein), ADH1C, DJ-1, EIF4G1, FBXO7, GBA/GBAP1, GIGYF2, HTRA2, LRRK2 [ 114 ], MAPT, PARK2, PARK7 [ 115 ], PRKN, PINK1, PLA2G6, UCHL1 , and VPS35 [ 116 ]. For example, several mutations to LRRK2 , encoding the leucine-rich repeat kinase 2 (LRRK2), are associated with PD and it has been reported as a significant factor for drug resistance [ 117 , 118 ].…”

Association study of DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 with Parkinson’s disease

“…GIGYF2 was initially reported in a cohort composed of Italian and French PD patients (Lautier et al, 2008), yet subsequent studies in Portuguese and US cohorts did not find evidence of association with PD (Bras et al, 2009). Numerous additional studies, including in a different Italian cohort and multiple other ethnicities, also failed to identify an association of GIGYF2 variants with PD (Bartonikova et al, 2018; Bonetti et al, 2009; Di Fonzo et al, 2009; Guo et al, 2009; Huo et al, 2017; Lesage et al, 2010; Li et al, 2010; Meeus et al, 2011; Nichols et al, 2009; Samaranch et al, 2010; Tan et al, 2009; Tan and Schapira, 2010; Tian et al, 2012; Vilarino-Guell et al, 2009; Wang, L. et al, 2010; Wang, L. et al, 2011; Yang et al, 2019; Zhang et al, 2015; Zhang et al, 2009; Zimprich et al, 2009). It is therefore very unlikely that GIGYF2 is associated with PD.…”

“…Their discovery shares several similarities, including the presumed role of loss-of-function, missense mutations and dominant heritability (Nalls et al, 2019). Subsequent studies, in many cases, failed to replicate the association of these genes with PD (Bartonikova et al, 2018; Gagliardi et al, 2018; Kruger et al, 2011; Nuytemans et al, 2013; Sun et al, 2014). However, ongoing studies, including those using cellular and animal models, continue to refer to these genes as PD-associated genes, and to invoke their function in PD-related mechanisms (Chen et al, 2018; Tran et al, 2018).…”