2 research outputs found
New PNM Mutation in SUP35
A number of [PSI+]-no-more (PNM) mutations, eliminating [PSI+] prion, were previously
described in SUP35. In this study, we designed and analyzed a new PNM mutation
based on the parallel in-register β-structure of Sup35 prion fibrils suggested by the
known experimental data. In such an arrangement, substitution of non-charged residues
by charged ones may destabilize the fibril structure. We introduced Q33K/A34K amino
acid substitutions into the Sup35 protein, corresponding allele was called sup35-M0.
The mutagenized residues were chosen based on ArchCandy in silico prediction of high
inhibitory effect on the amyloidogenic potential of Sup35. The experiments confirmed that
Sup35-M0 leads to the elimination of [PSI+] with high efficiency. Our data suggested that
the elimination of the [PSI+] prion is associated with the decreased aggregation properties
of the protein. The new mutation can induce the prion with very low efficiency and is able
to propagate only weak [PSI+] prion variants. We also showed that Sup35-M0 protein
co-aggregates with the wild-type Sup35 in vivo. Moreover, our data confirmed the utility
of the strategy of substitution of non-charged residues by charged ones to design new
mutations to inhibit a prion formationRFBR grant 19-04-00173, RFBR grant 17-54-150002, and PRC CNRS
grant PRC1524,18-34-00536, RSF grant 18-14-0005
Whole-exome sequencing provides insights into monogenic disease prevalence in Northwest Russia
Abstract Background Allele frequency data from large exome and genome aggregation projects such as the Genome Aggregation Database (gnomAD) are of ultimate importance to the interpretation of medical resequencing data. However, allele frequencies might significantly differ in poorly studied populations that are underrepresented in large‐scale projects, such as the Russian population. Methods In this work, we leveraged our access to a large dataset of 694 exome samples to analyze genetic variation in the Northwest Russia. We compared the spectrum of genetic variants to the dbSNP build 151, and made estimates of ClinVar‐based autosomal recessive (AR) disease allele prevalence as compared to gnomAD r. 2.1. Results An estimated 9.3% of discovered variants were not present in dbSNP. We report statistically significant overrepresentation of pathogenic variants for several Mendelian disorders, including phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), kyphoscoliosis type of Ehlers‐Danlos syndrome (FKBP14, rs542489955), and several other recessive pathologies. We also make primary estimates of monogenic disease incidence in the population, with retinal dystrophy, cystic fibrosis, and phenylketonuria being the most frequent AR pathologies. Conclusion Our observations demonstrate the utility of population‐specific allele frequency data to the diagnosis of monogenic disorders using high‐throughput technologies