• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • Although the interactions of PhLP with G and its other


    Although the interactions of PhLP with Gβγ and its other partners have been convincingly documented through in vitro studies, it is not clear how PhLP controls AZD1208 signaling in vivo. C. elegans provides a powerful genetic model to analyze Phosducin function and study its interacting partners in signaling pathways. In this report, we describe the phenotypic and molecular characterization of mau-8, a maternal-effect uncoordinated mutant of C. elegans. Our results indicate that the mau-8 gene encodes a ubiquitous Phosducin-like Protein that regulates various physiological functions in the nematode.
    Materials and methods
    Introduction Prion diseases are transmissible, fatal neurodegenerative conditions affecting humans and animals (Collinge, 2001). The infectious agent is composed of assemblies of abnormally folded host-encoded prion protein (PrP), some of which acquire protease resistance, designated as PrPSc (Prusiner, 1998). Human prion diseases most commonly occur sporadically but can be acquired through dietary exposure or iatrogenesis. Inherited prion diseases (IPDs) comprise 10%–15% of the total annual incidence and are associated with coding mutations in the prion protein gene (PRNP) (Mead, 2006). Clinical phenotypes of IPD are highly heterogeneous and include rapidly progressive forms of dementia and/or ataxia (indistinguishable from sporadic Creutzfeldt-Jakob disease [CJD]), fatal familial insomnia and more slowly progressive syndromes such as Gerstmann-Straussler-Scheinker disease and PrP systemic amyloidosis (Mead and Reilly, 2015, Mead et al., 2013). A great deal is now known about normal variation of PRNP in different populations (Beck et al., 2010, Minikel et al., 2016). Situated on one end of the spectrum are commonly occurring benign polymorphisms, some of which can modify prion disease susceptibility and clinical phenotype, while on the other lies well-defined highly penetrant variants such as the P102L, E200K, D178N, and large octapeptide repeat insertions. Then there are partially penetrant variants such as V210I found both in control and patient populations that are associated with increased risk but not inevitable disease (Minikel et al., 2016). The advent of low-cost, high-throughput genomic sequencing technologies has led to large-scale population genomic databases that can be used to estimate penetrance. Such an approach used recently led to reclassifying several PRNP sequence variants, previously reported to be pathogenic in the literature, as likely to be either low risk or even benign (Minikel et al., 2016). The most challenging ones to classify are the extremely rare variants found in only a few patients and controls. Causal analyses of these rare PRNP variants seen in CJD, particularly in the absence of family history, have historically been biased toward overcalling of pathogenicity (Minikel et al., 2016). Erroneous assignation of pathogenicity and penetrance to a benign variant may not only lead to unnecessary psychological distress but could also misdirect genetic counseling for the patients' relatives. At the research level, analysis of sets of variants classified as accurately as possible by pathogenicity may help uncover fundamental mechanisms of prion disease. Here, we illustrate our practice in estimation of the causality of the novel PRNP variant T201S. We used multiple lines of evidence and address the challenges faced with interpretation of rare gene variants that may be applicable to other PRNP variants and those in genes related to other neurodegenerative diseases.
    Discussion The clinical picture of IPD caused by highly penetrant PRNP mutations such as E200K, D178N, and P102L can be indistinguishable from that of sCJD. Both our cases had acute clinical onsets within the peak age range of onset reported for sCJD, followed by rapid neurological decline and death within 3 months. Together with restricted diffusion affecting the anterior basal ganglia and cortical ribboning on MRI, generalized periodic complexes on EEG (case 2), cerebrospinal fluid protein 14.3.3 positivity (case 1), and neuropathological findings (case 1), both these patients fulfilled diagnostic criteria for probable sCJD (Zerr et al., 2009) had PRNP sequencing not been carried out.