Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population

The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism

The repertoire of G protein-coupled receptors in the human parasite Schistosoma mansoni and the model organism Schmidtea mediterranea.

<p>Abstract</p> <p>Background</p> <p>G protein-coupled receptors (GPCRs) constitute one of the largest groupings of eukaryotic proteins, and represent a particularly lucrative set of pharmaceutical targets. They play an important role in eukaryotic signal transduction and physiology, mediating cellular responses to a diverse range of extracellular stimuli. The phylum Platyhelminthes is of considerable medical and biological importance, housing major pathogens as well as established model organisms. The recent availability of genomic data for the human blood fluke <it>Schistosoma mansoni </it>and the model planarian <it>Schmidtea mediterranea </it>paves the way for the first comprehensive effort to identify and analyze GPCRs in this important phylum.</p> <p>Results</p> <p>Application of a novel transmembrane-oriented approach to receptor mining led to the discovery of 117 <it>S. mansoni </it>GPCRs, representing all of the major families; 105 <it>Rhodopsin</it>, 2 <it>Glutamate</it>, 3 <it>Adhesion</it>, 2 <it>Secretin </it>and 5 <it>Frizzled</it>. Similarly, 418 <it>Rhodopsin</it>, 9 <it>Glutamate</it>, 21 <it>Adhesion</it>, 1 <it>Secretin </it>and 11 <it>Frizzled S. mediterranea </it>receptors were identified. Among these, we report the identification of novel receptor groupings, including a large and highly-diverged Platyhelminth-specific <it>Rhodopsin </it>subfamily, a planarian-specific <it>Adhesion</it>-like family, and atypical <it>Glutamate</it>-like receptors. Phylogenetic analysis was carried out following extensive gene curation. Support vector machines (SVMs) were trained and used for ligand-based classification of full-length <it>Rhodopsin </it>GPCRs, complementing phylogenetic and homology-based classification.</p> <p>Conclusions</p> <p>Genome-wide investigation of GPCRs in two platyhelminth genomes reveals an extensive and complex receptor signaling repertoire with many unique features. This work provides important sequence and functional leads for understanding basic flatworm receptor biology, and sheds light on a lucrative set of anthelmintic drug targets.</p