Activating and inactivating mutations in numerous human G protein-coupled receptors (GPCRs) are associated with a wide range of disease phenotypes. Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations, many of which were biochemically characterized, along with known GPCR structures and current models of GPCR activation, to understand the molecular mechanisms yielding pathological phenotypes. Based on this mechanistic understanding we also propose different therapeutic approaches, both conventional, using small molecule ligands, and novel, involving gene therapy.
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http://dx.doi.org/10.1016/j.gendis.2015.02.005 | DOI Listing |
Curr Protoc
January 2025
Myriad Genetic Laboratories, Inc., Salt Lake City, Utah.
Balanced translocation carriers experience elevated reproductive risks, including pregnancy loss and children with anomalies due to generating chromosomally unbalanced gametes. While understanding the likelihood of producing unbalanced conceptuses is critical for individuals to make reproductive decisions, risk estimates are difficult to obtain as most balanced translocations are unique. To improve reproductive risk estimates, Drs.
View Article and Find Full Text PDFThe expression of genomically-encoded information is not error-free. Transcript-error rates are dramatically higher than DNA-level mutation rates, and despite their transient nature, the steady-state load of such errors must impose some burden on cellular performance. However, a broad perspective on the degree to which transcript-error rates are constrained by natural selection and diverge among lineages remains to be developed.
View Article and Find Full Text PDFJ Allergy Clin Immunol Glob
February 2025
Department of Molecular Medicine, Sapienza University, Rome, Italy.
Background: Many patients with X-linked agammaglobulinemia (XLA) nowadays have reached adulthood, as well as their sisters, possibly carriers of a deleterious Bruton tyrosine kinase variant. Studies on motherhood outcomes in families with XLA are lacking.
Objective: We sought to investigate adherence to carrier status screening, interest in preconception and prenatal genetic counseling, and reproductive decisions in relatives with XLA.
Bioinform Adv
January 2025
Digital Technologies Research Centre, National Research Council of Canada, Ottawa, ON K1K 4P7, Canada.
Motivation: Missing values are prevalent in high-throughput measurements due to various experimental or analytical reasons. Imputation, the process of replacing missing values in a dataset with estimated values, plays an important role in multivariate and machine learning analyses. The three missingness patterns, including missing completely at random, missing at random, and missing not at random, describe unique dependencies between the missing and observed data.
View Article and Find Full Text PDFNat Commun
January 2025
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power.
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