RESUMEN
BACKGROUND: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. METHODS: Within the period of 2014-2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. RESULTS: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. CONCLUSIONS: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.
RESUMEN
Circadian clocks are synchronized by the natural day/night and temperature cycles. Our previous work demonstrated that synchronization by temperature is a tissue autonomous process, similar to synchronization by light. We show here that this is indeed the case, with the important exception of the brain. Using luciferase imaging we demonstrate that brain clock neurons depend on signals from peripheral tissues in order to be synchronized by temperature. Reducing the function of the gene nocte in chordotonal organs changes their structure and function and dramatically interferes with temperature synchronization of behavioral activity. Other mutants known to affect the function of these sensory organs also interfere with temperature synchronization, demonstrating the importance of nocte in this process and identifying the chordotonal organs as relevant sensory structures. Our work reveals surprising and important mechanistic differences between light- and temperature-synchronization and advances our understanding of how clock resetting is accomplished in nature.
Asunto(s)
Vías Aferentes/fisiología , Relojes Biológicos/fisiología , Ritmo Circadiano/fisiología , Proteínas de Drosophila/fisiología , Temperatura , Adaptación Ocular/genética , Animales , Animales Modificados Genéticamente , Conducta Animal , Relojes Biológicos/genética , Encéfalo/citología , Ritmo Circadiano/genética , Drosophila , Proteínas de Drosophila/genética , Femenino , Regulación de la Expresión Génica/fisiología , Proteínas Fluorescentes Verdes/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Mutación/genética , Neuronas/fisiología , Técnicas de Cultivo de Órganos , Proteínas Circadianas Period , Interferencia de ARN/fisiología , Órganos de los Sentidos/metabolismo , Sensación Térmica/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Circadian clocks are synchronized by both light:dark cycles and by temperature fluctuations. Although it has long been known that temperature cycles can robustly entrain Drosophila locomotor rhythms, nothing is known about the molecular mechanisms involved. RESULTS: We show here that temperature cycles induce synchronized behavioral rhythms and oscillations of the clock proteins PERIOD and TIMELESS in constant light, a situation that normally leads to molecular and behavioral arrhythmicity. We show that expression of the Drosophila clock gene period can be entrained by temperature cycles in cultured body parts and isolated brains. Further, we show that the phospholipase C encoded by the norpA gene contributes to thermal entrainment, suggesting that a receptor-coupled transduction cascade signals temperature changes to the circadian clock. We initiated the further genetic dissection of temperature-entrainment and isolated the novel Drosophila mutation nocte, which is defective in molecular and behavioral entrainment by temperature cycles but synchronizes normally to light:dark cycles. CONCLUSIONS: We conclude that temperature synchronization of the circadian clock is a tissue-autonomous process that is able to override the arrhythmia-inducing effects of constant light. Our data suggest that it involves a cell-autonomous signal-transduction cascade from a thermal receptor to the circadian clock. This process includes the function of phospholipase C and the product specified by the novel mutation nocte.
