Calcium channels are crucial to a number of cellular functions. The high voltage-gated calcium channel family comprise four heteromeric channels (Cav1.1-1.4) that function in a similar manner, but that have distinct expression profiles. Three of the pore-forming α1 subunits are located on autosomes and the forth on the X chromosome, which has consequences for the type of pathogenic mutation and the disease mechanism associated with each gene. Mutations in this family of channels are associated with malignant hyperthermia (Cav1.1), various QT syndromes (Cav1.2), deafness (Cav1.3), and incomplete congenital stationary night blindness (iCSNB; Cav1.4). In this study we performed a bioinformatic analysis on reported mutations in all four Cav α1 subunits and correlated these with variant frequency in the general population, phenotype and the effect on channel conductance to produce a comprehensive composite Cav1 mutation analysis. We describe regions of mutation clustering, identify conserved residues that are mutated in multiple family members and regions likely to cause a loss- or gain-of-function in Cav1.4. Our research highlights that therapeutic treatments for each of the Cav1 channels will have to consider channel-specific mechanisms, especially for the treatment of X-linked iCSNB.
Pathogenic, generally loss-of-function, variants in CACNA1F, encoding the Cav1.4α1 calcium channel, underlie congenital stationary night blindness type 2 (CSNB2), a rare inherited retinal disorder associated with visual disability. To establish the underlying pathomechanism, we investigated 10 clinically derived CACNA1F missense variants located across pore-forming domains, connecting loops, and the carboxy-tail domain of the Cav1.4α subunit. Homology modeling showed that all variants cause steric clashes; informatics analysis correctly predicted pathogenicity for 7/10 variants. In vitro analyses demonstrated that all variants cause a decrease in current, global expression, and protein stability and act through a loss-of-function mechanism and suggested that the mutant Cav1.4α proteins were degraded by the proteasome. We showed that the reduced current for these variants could be significantly increased through treatment with clinical proteasome inhibitors. In addition to facilitating clinical interpretation, these studies suggest that proteasomal inhibition represents an avenue of potential therapeutic intervention for CSNB2.
Post partum albino mice were injected intraperitoneally with lP4Ce-citrate at different times during the lactation period. Twenty-four hours and 4 weeks later, the suckling neonates were sacrificed and the 144Ce content in their digestive tract, liver and carcass determined by gamma counting. The fraction 0f14~Ce absorbed from the gastrointestinal tract was calculated. It is one to two orders of magnitude above the currently accepted values for gastrointestinal absorption of lanthanides in adult mice. The discriminatory characteristics of the gastrointestinal tract in early life, as derived from our experiments, are discussed in the light of other relevant investigations.
The incidence and prognosis of thrombocytopenia in critically ill patients with bloodstream infection (BSI) is not well delineated in the pediatric intensive care unit (PICU) setting. We assessed these variables in our PICU and sought to determine whether thrombocytopenia could serve as a prognostic marker for length of stay (LOS). The study was conducted at the medical PICU of a university hospital, on all critically ill pediatric patients consecutively admitted during a 3-year period. Patient surveillance and data collection have been used to identify the risk factors during the study period. The main outcomes were BSI incidence and implication on morbidity and LOS. Data from 2,349 PICU patients was analyzed. The overall incidence of BSI was 3.9% (93/2,349). Overall, 85 of 93 patients (91.4%) with BSI survived and 8 patients died (8.6% mortality rate). The overall incidence of thrombocytopenia among these 93 patients was 54.8% (51/93) and 100% (8/8) for the nonsurvivors. Out of the 85 survivors, 27 thrombocytopenic patients were hospitalized for >14 days versus 14 of nonthrombocytopenic patients (p = 0.007). Thrombocytopenia was associated with borderline significance with an increased LOS (adjusted odds ratio = 3.00, 95% confidence interval: 0.93–9.71, p = 0.066). Thrombocytopenia is common in critically ill pediatric patients with BSI and constitutes a simple and readily available risk marker for PICU LOS.
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