Calcium (Ca2+) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store‐operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain‐of‐function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss‐of‐function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation‐dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non‐muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.
Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases.
Routine hemodialysis is associated with an increase in left ventricular contractility that is independent of a change in preload, but the mechanisms responsible are unknown. We investigated the importance of three distinct effects that regularly occur in hemodialysis and could potentially improve left ventricular contractility: the removal of uremic toxins, the increase in the plasma ionized calcium concentration, and the increase in the plasma bicarbonate concentration. Three different dialysates were used for each of eight stable patients on long-term hemodialysis, and left ventricular contractility was assessed by two-dimensional echocardiography before and after each dialysis. In the first procedure neither the ionized calcium nor the bicarbonate concentration was allowed to increase, and left ventricular contractility did not improve. In the second procedure, ionized calcium increased (from 4.4 to 5.4 mg per deciliter, P less than 0.001), bicarbonate concentration was held constant, and contractility increased (from 0.74 to 0.93 circumferences per second, P less than 0.005). In the third procedure, ionized calcium was kept constant, the bicarbonate concentration increased (from 19 to 24 mmol per liter, P less than 0.001), but contractility did not increase. These results suggest that the increase in ionized calcium that occurs in regular dialysis is a key factor in the improvement in left ventricular contractility observed during the procedure.
SUMMARY The normal human left ventricular response to large variations in preload was studied in 12 young men. M-mode echocardiograms were recorded at supine rest and compared with studies obtained during head-down tilt (HDT) at 50 and during progressive lower body negative pressure (LBNP) to -40 mm Hg.During HDT, end-diastolic volume (EDV) increased 23% (p < 0.001), stroke volume (SV) increased 35% (p < 0.001) and ejection fraction (EF) increased 10% (p < 0.05). Heart rate (HR) decreased by 5 beats/min (p < 0.025). During LBNP, EDV decreased 28% (p < 0.001), end-systolic volume (ESV) decreased 21% (p < 0.001) and SV decreased 33% (p < 0.001). LBNP was accompanied by a minor increase in HR (9 beats/min,p < 0.001) and a small increase in systolic blood pressure (11 mm Hg, p < 0.01). Comparisons between measurements obtained during HDT and LBNP showed significant differences in EDV, ESV, SV, EF, HR and diastolic blood pressure. The mean velocity of circumferential fiber shortening was unchanged. The combined data from the control studies and the interventions defined the normal left ventricular function curve as an exponential function where SV = 0.36 EDVY'' ml (r = 0.93, p < 0.001), which was not significantly different from the linear regression SV = 0.6 EDV + 0.57 (r = 0.92, p < 0.001).Our data indicate that the mean velocity of circumferential fiber shortening is an index of contractile state that is independent of preload, whereas other echocardiographic measurements are significantly altered by large changes in preload.THE RESPONSE of the normal human left ventricle to changes in preload has been studied by various methods.1 12 However, the range of preload variation has been limited, and the results have often been difficult to interpret due to simultaneous changes in arterial blood pressure and heart rate. Previous studies in our laboratory showed that large variations in preload with minimal effects on heart rate or arterial blood pressure can be introduced noninvasively by head-down tilt and lower body negative pressure (LBNP).12, 13 The primary purpose of the study was to define echocardiographically the extreme ranges of the normal relationship between left ventricular end-diastolic dimensions and stroke volume (i.e., a classic Frank-Starling curve). We also studied the effect of wide variations in preload on commonly used indexes of myocardial contractile state. Materials and MethodsTwelve normal male volunteers, ages 22-31 years, were studied. Details of the protocol were explained, and each subject gave informed written consent. The study protocol was reviewed and approved by the sity of Texas Health Science Center at Dallas. The subjects underwent physical examination and were in excellent health. No medications were being taken at the time of the studies. Echocardiograms were obtained using a Unirad 100 series ultrasonoscope, model 902, with a 2.25-MHz, 13-mm-diameter transducer collimated to 7.5 cm, with a repetition rate of 1000 Hz. M-mode tracings and an ECG were recorded on a Honeywell 1856A s...
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