Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel ...gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
While boundary and forcing conditions influence the average location of a shoreline in deltaic systems, internal morphodynamics can drive high‐magnitude deviations from the long‐term trend. Here we ...explore the role of sediment cohesion on these morphodynamics using physical experiments. Specifically, we explore the role of sediment cohesion on the scales of autogenic shoreline transgressions and regressions. Results indicate that sediment cohesion enhances the time and space scales associated with autogenic cycles of channel formation, elongation, and abandonment. In systems with high sediment cohesion, this cycle can drive shoreline transgressions that produce flooding surfaces in the resulting stratigraphy which could be confused with surfaces produced by increases in sea level rise or subsidence rates. Enhanced channelization resulting from sediment cohesion also increases the pumping of fine‐grained sediment into the marine realm, where it can bypass the delta foreset, thus decreasing total delta sediment retention rate.
Key Points
Sediment cohesion on its own is inversely related to deltaic sediment retention
Sediment cohesion increases scales of autogenic shoreline transgressions
Autogenic shoreline transgressions scale with backwater length in deltas
The mitochondria‐associated membrane (MAM) is a domain of the endoplasmic reticulum (ER) that mediates the exchange of ions, lipids and metabolites between the ER and mitochondria. ER chaperones and ...oxidoreductases are critical components of the MAM. However, the localization motifs and mechanisms for most MAM proteins have remained elusive. Using two highly related ER oxidoreductases as a model system, we now show that palmitoylation enriches ER‐localized proteins on the MAM. We demonstrate that palmitoylation of cysteine residue(s) adjacent to the membrane‐spanning domain promotes MAM enrichment of the transmembrane thioredoxin family protein TMX. In addition to TMX, our results also show that calnexin shuttles between the rough ER and the MAM depending on its palmitoylation status. Mutation of the TMX and calnexin palmitoylation sites and chemical interference with palmitoylation disrupt their MAM enrichment. Since ER‐localized heme oxygenase‐1, but not cytosolic GRP75 require palmitoylation to reside on the MAM, our findings identify palmitoylation as key for MAM enrichment of ER membrane proteins.
Mitochondria‐associated ER membranes (MAM) recently emerged as critical for cellular signal transduction and metabolism. This study identifies palmitoylation as novel mechanism for targeted localization of ER‐transmembrane proteins to MAM domains.
Mutations in the gene encoding tripartite motif protein 32 (TRIM32) cause two seemingly diverse diseases: limb-girdle muscular dystrophy type 2H (LGMD2H) or sarcotubular myopathy (STM) and ...Bardet–Biedl syndrome type 11(BBS11). Although TRIM32 is involved in protein ubiquitination, its substrates and the molecular consequences of disease-causing mutations are poorly understood. In this paper, we show that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. Using the yeast two-hybrid system, we found that TRIM32 binds and ubiquitinates dysbindin, a protein implicated in the genetic aetiology of schizophrenia, augmenting its degradation. Small-interfering RNA-mediated knock-down of TRIM32 in myoblasts resulted in elevated levels of dysbindin. Importantly, the LGMD2H/STM-associated TRIM32 mutations, D487N and R394H impair ubiquitin ligase activity towards dysbindin and were mislocalized in heterologous cells. These mutants were able to self-associate and also co-immunoprecipitated with wild-type TRIM32 in transfected cells. Furthermore, the D487N mutant could bind to both dysbindin and its E2 enzyme but was defective in monoubiquitination. In contrast, the BBS11 mutant P130S did not show any biochemical differences compared with the wild-type protein. Our data identify TRIM32 as a regulator of dysbindin and demonstrate that the LGMD2H/STM mutations may impair substrate ubiquitination.
To report on a patient with spinocerebellar ataxia type 14 (SCA14) and macular dystrophy with identification of a novel
variant.
Case report.
A 63-year-old female with molecularly confirmed SCA14 ...presented with symmetric pigmentary disturbances in a perifoveal distribution resembling a pattern macular dystrophy. She had no history of using medications with recognized toxic macular effects. Subsequent genetic testing confirmed a novel heterozygous missense variant of unknown significance in
(
: c.694 G>A, p.(Ala232Thr)).
To our knowledge, this is the first case of macular dystrophy identified in a patient with SCA14. While it is possible that the macular dystrophy observed in this patient might be an under-reported phenotype associated with SCA14, the pattern of macular changes is consistent with
-related disorders. The identified missense variant is predicted to be damaging by most in silico models, and the residue is highly conserved, adding support to a dual genetic diagnosis in this case.
The mitochondria-associated membrane (MAM) has emerged as an endoplasmic reticulum (ER) signaling hub that accommodates ER chaperones, including the lectin calnexin. At the MAM, these chaperones ...control ER homeostasis but also play a role in the onset of ER stress-mediated apoptosis, likely through the modulation of ER calcium signaling. These opposing roles of MAM-localized chaperones suggest the existence of mechanisms that regulate the composition and the properties of ER membrane domains. Our results now show that the GTPase Rab32 localizes to the ER and mitochondria, and we identify this protein as a regulator of MAM properties. Consistent with such a role, Rab32 modulates ER calcium handling and disrupts the specific enrichment of calnexin on the MAM, while not affecting the ER distribution of protein-disulfide isomerase and mitofusin-2. Furthermore, Rab32 determines the targeting of PKA to mitochondrial and ER membranes and through its overexpression or inactivation increases the phosphorylation of Bad and of Drp1. Through a combination of its functions as a PKA-anchoring protein and a regulator of MAM properties, the activity and expression level of Rab32 determine the speed of apoptosis onset.
The palmitoylation of calnexin serves to enrich calnexin on the mitochondria-associated membrane (MAM). Given a lack of information on the significance of this finding, we have investigated how this ...endoplasmic reticulum (ER)-internal sorting signal affects the functions of calnexin. Our results demonstrate that palmitoylated calnexin interacts with sarcoendoplasmic reticulum (SR) Ca(2+) transport ATPase (SERCA) 2b and that this interaction determines ER Ca(2+) content and the regulation of ER-mitochondria Ca(2+) crosstalk. In contrast, non-palmitoylated calnexin interacts with the oxidoreductase ERp57 and performs its well-known function in quality control. Interestingly, our results also show that calnexin palmitoylation is an ER-stress-dependent mechanism. Following a short-term ER stress, calnexin quickly becomes less palmitoylated, which shifts its function from the regulation of Ca(2+) signaling towards chaperoning and quality control of known substrates. These changes also correlate with a preferential distribution of calnexin to the MAM under resting conditions, or the rough ER and ER quality control compartment (ERQC) following ER stress. Our results have therefore identified the switch that assigns calnexin either to Ca(2+) signaling or to protein chaperoning.
To analyze the single surgery success rate and anterior segment complications related to phacoemulsification and intraocular lens implantation in a series of patients undergoing phacovitrectomy for ...all types of primary rhegmatogenous retinal detachment.
We performed a retrospective interventional case series on 302 eyes undergoing phacovitrectomy for primary rhegmatogenous retinal detachment repair between November 1, 2016, and February 2, 2019, in Edmonton, Canada. Primary outcomes included single surgery retinal reattachment rate and anterior segment complications. Secondary outcomes included the effects of proliferative vitreoretinopathy and macula and/or peripheral internal limiting membrane peeling on the rate of surgical success.
The single surgery success rate of phacovitrectomy for all types of primary rhegmatogenous retinal detachment was 85.1%. The presence of proliferative vitreoretinopathy was associated with lower surgical success (odds ratio, 0.33; P = 0.01). Macular internal limiting membrane peeling was associated with higher surgical success (odds ratio, 2.4; P = 0.05). Anterior segment complications included posterior capsular opacification (28.8%), posterior synechiae (10.9%), and posterior capsular rupture (2.3%).
Phacovitrectomy is a safe and effective treatment option for the primary repair of rhegmatogenous retinal detachments. This study provides evidence to support the safe incorporation of phacoemulsification and intraocular lens implantation with retinal surgery.
To identify and characterize the incidence and correlates of open-globe injuries documented at the Eye Institute of Alberta (EIA) at the Royal Alexandra Hospital in Edmonton.
A 10-year single-centre ...retrospective chart review.
All patients who underwent traumatic open-globe injury repair at EIA from January 2009–December 2018 were identified using key search terms. Charts were individually assessed for key demographic variables, including mechanism and location of injury. Patterns in open-globe injury incidence over the 10-year period and across demographics were assessed using Poisson regression. Associations between key demographic variables also were analyzed.
In total, 551 traumatic open-globe injuries were treated at the EIA from January 2009–December 2018, resulting in an average of 4.63 injuries per month over the 10-year period. Mean patient age was 42 ± 21.56 years. The number of males (n = 442) presenting for open-globe injury repair was 3.9 times higher than that for females (n = 114). Among patients for whom use of eye protection was recorded (n = 186), only 11% reported using eye protection at the time of the trauma. The incidence rate of injuries with zone 3 involvement was significantly higher in males (41.4%) than in females (29.8%).
Open-globe injuries remain a significant source of ocular morbidity at EIA, averaging just over 1 emergency case a week. Given the strong association with sex and the infrequent use of eye protection, targeted public health strategies are necessary to mitigate the risk of these sight-threatening injuries.
Identifier et décrire l'incidence et les corrélats des blessures à globe ouvert consignées à l'Eye Institute of Alberta (EIA) du Royal Alexandra Hospital, à Edmonton.
Revue de rétrospective des dossiers médicaux réalisée dans un seul centre sur une période de 10 ans.
Tous les patients traités à l'EIA entre janvier 2009 et décembre 2018 en raison d'une blessure traumatique à globe ouvert ont été recensés dans le cadre d'une recherche par mots clés. On a extrait des dossiers les données démographiques clés, notamment le type de blessure et sa localisation. On a eu recours à une régression de Poisson afin de mettre au jour les tendances en ce qui a trait à l'incidence de blessures à globe ouvert sur les 10 ans de l’étude et dans l'ensemble des statistiques démographiques. On a en outre analysé les associations entre les variables démographiques clés.
Au total, 551 blessures traumatiques à globe ouvert ont été traitées à l'EIA entre janvier 2009 et décembre 2018, d'où une moyenne mensuelle de 4,63 blessures pendant les 10 années de l’étude. L’âge moyen des patients était de 42 ± 21,56 ans; on compte 3,9 fois plus d'hommes (n = 442) qui ont eu besoin d'un traitement en raison d'une blessure à globe ouvert que de femmes (n = 114). Parmi les patients pour lesquels une forme de protection oculaire avait été notée (n = 186), seulement 11 % ont affirmé porter leur protection oculaire au moment du traumatisme. Le taux d'incidence de plaies de zone 3 était significativement plus élevé chez les hommes (41,4 %) que chez les femmes (29,8 %).
Les blessures à globe ouvert demeurent une source importante de morbidité oculaire à l'EIA, qui traite en moyenne un peu plus de 1 cas urgent par semaine. Compte tenu de la forte association avec le sexe et l'utilisation peu fréquente de modalités de protection oculaire, des stratégies ciblées de sensibilisation du public sont nécessaires pour réduire le risque de survenue de ces blessures qui menacent la vision.
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