RESUMEN
Familial mediterranean fever (FMF) is a genetic autoinflammatory disease typically diagnosed in childhood. In this study, we aimed to investigate the demographic, clinical, and genetic characteristics of patients aged 18 years and older who were diagnosed with FMF. Patients diagnosed with FMF between 2014 and 2022 at Karadeniz Technical University Faculty of Medicine Hospital were included in the study. Patients were divided into 2 groups based on the age of disease onset. Group I included patients with adult-onset (ages 18-40), while group II comprised patients with late onset (ages 40 and above). Subsequently, the 2 groups were compared. A total of 150 patients with a mean age of 32 (18-79) were included in the study. There were 116 patients in group I and 34 (22.7%) in group II. The most common presenting complaint was abdominal pain (91.3%), and the most prevalent complication was amyloidosis (4.7%). No significant differences were observed between age groups regarding clinical findings and symptoms. The most frequent homozygous mutations were M694V (9.3%) and R202Q (1.8%), while the heterozygous mutations were M694V (37.3%) and R202Q (35.5%), respectively. The rate of M694V gene positivity in the adult-onset group was significantly higher compared to the lateonset group (52.9% and 25%, respectively, P = .020). There does not appear to be a significant difference in clinical signs and symptoms between adult-onset and late-onset FMF patients. The higher rate of M694V gene positivity in the adult-onset group suggests that the M694V mutation may be responsible for the early expression of the disease.
Asunto(s)
Edad de Inicio , Fiebre Mediterránea Familiar , Mutación , Pirina , Humanos , Fiebre Mediterránea Familiar/genética , Adulto , Masculino , Femenino , Persona de Mediana Edad , Adulto Joven , Adolescente , Anciano , Pirina/genética , Turquía/epidemiología , Dolor Abdominal/etiología , Amiloidosis/genética , Homocigoto , HeterocigotoRESUMEN
Amyloidosis is a complex group of rare disorders characterized by the deposition of misfolded proteins in the extracellular space of various tissues and organs, leading to progressive organ dysfunction. The kidneys constitute a very common site affected, most notably by immunoglobulin-mediated (light chain, heavy chain, and light and heavy chain amyloidosis), but other types that include serum amyloid A (AA) amyloidosis and leukocyte chemotactic factor 2 amyloidosis, along with mutant proteins in several hereditary forms of amyloidosis such as transthyretin, fibrinogen α-chain, gelsolin, lysozyme, and apolipoproteins AI/AII/AIV/CII/CIII amyloidosis have been incriminated as well. The clinical presentation is variable and can range from minimal proteinuria for leukocyte chemotactic factor 2 amyloidosis to a full-blown nephrotic syndrome for AA amyloidosis. Clinical correlation, genetic analysis, and adequate tissue typing through a kidney biopsy are essential to make the correct diagnosis, especially when a family history of amyloidosis is absent. Except for AA and transthyretin amyloidosis, the treatment is usually purely supportive. Kidney transplantation is an acceptable form of treatment for end-stage kidney disease in all types of non-Ig-mediated renal amyloidosis.
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Amiloidosis , Humanos , Amiloidosis/diagnóstico , Amiloidosis/genética , Amiloidosis/inmunología , Amiloidosis/metabolismo , Enfermedades Renales/diagnóstico , Enfermedades Renales/patología , Enfermedades Renales/genética , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Trasplante de Riñón , Riñón/patología , Riñón/metabolismo , Riñón/inmunología , Proteína Amiloide A SéricaRESUMEN
ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found unique structural variabilities in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.
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Amiloide , Microscopía por Crioelectrón , Miocardio , Humanos , Amiloide/metabolismo , Amiloide/química , Amiloide/ultraestructura , Miocardio/patología , Miocardio/ultraestructura , Prealbúmina/genética , Prealbúmina/metabolismo , Prealbúmina/química , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Amiloidosis/metabolismo , Amiloidosis/patología , Amiloidosis/genética , Mutación , Cardiomiopatías/genética , Cardiomiopatías/patología , Cardiomiopatías/metabolismoRESUMEN
Amyloid neuropathy is caused by deposition of insoluble ß-pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light-chain amyloidosis, a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood-nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early-onset Val30Met ATTRv, whereas other ATTRv and light-chain amyloidosis often present with large- and small-fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone-avid radiotracer cardiac imaging. Treatment of light-chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5-year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423-440.
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Neuropatías Amiloides Familiares , Neuropatías Amiloides , Humanos , Neuropatías Amiloides Familiares/terapia , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/fisiopatología , Neuropatías Amiloides/terapia , Neuropatías Amiloides/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/fisiopatología , Amiloidosis/terapia , Amiloidosis/genética , Prealbúmina/genéticaRESUMEN
Renal amyloidosis is a set of complex disorders characterized by the deposition of amyloid proteins in the kidneys, which causes gradual organ damage and potential kidney failure. Recent developments in diagnostic methods, particularly mass spectrometry and proteome profiling, have greatly improved the accuracy of amyloid typing, which is critical for disease management. These technologies provide extensive insights into the specific proteins involved, allowing for more targeted treatment approaches and better patient results. Despite these advances, problems remain, owing to the heterogeneous composition of amyloid proteins and the varying efficacy of treatments based on amyloid type. Access to sophisticated diagnostics and therapy varies greatly, highlighting the global difference in renal amyloidosis management. Future research is needed to investigate next-generation sequencing and gene-editing technologies, like clustered regularly interspaced short palindromic repeats (CRISPR), which promise more profound insights into the genetic basis of amyloidosis.
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Amiloidosis , Enfermedades Renales , Humanos , Amiloidosis/diagnóstico , Amiloidosis/terapia , Amiloidosis/genética , Amiloidosis/metabolismo , Enfermedades Renales/diagnóstico , Enfermedades Renales/terapia , Enfermedades Renales/genética , Proteómica/métodos , Espectrometría de Masas/métodosRESUMEN
Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23â¯338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23â¯338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435â¯851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957â¯505 years of life (95% CI, 534â¯475-1â¯380â¯535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.
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Amiloidosis , Negro o Afroamericano , Cardiomiopatías , Insuficiencia Cardíaca , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Amiloidosis/etnología , Amiloidosis/genética , Negro o Afroamericano/genética , Cardiomiopatías/etnología , Cardiomiopatías/genética , Progresión de la Enfermedad , Insuficiencia Cardíaca/etnología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/mortalidad , Heterocigoto , Hospitalización/estadística & datos numéricos , Prealbúmina/genética , Volumen Sistólico , Estados Unidos/epidemiología , Costo de EnfermedadRESUMEN
Systemic amyloid A (AA) amyloidosis, which is considered the second most common form of systemic amyloidosis usually takes place several years prior to the occurrence of chronic inflammation, generally involving the kidney. Activated HSF1, which alleviated unfolded protein response (UPR) or enhanced HSR, is the potential therapeutic target of many diseases. However, the effect of HSF1 on AA amyloidosis remains unclear. This study focused on evaluating effect of HSF1 on AA amyloidosis based on HSF1 knockout mice. As a result, aggravated amyloid deposits and renal dysfunction have been found in HSF1 knockout mice. In progressive AA amyloidosis, HSF1 deficiency enhances serum amyloid A production might to lead to severe AA amyloid deposition in mice, which may be related to deactivated unfolded protein response as well as enhanced inflammation. Thus, HSF1 plays a significant role on UPR related pathway impacting AA amyloid deposition, which can mitigate amyloidogenic proteins from aggregation pathologically and is the possible way for intervening with the pathology of systemic amyloid disorder. In conclusion, HSF1 could not only serve as a new target for AA amyloidosis treatment in the future, but HSF1 knockout mice also can be considered as a valuable novel animal model for renal AA amyloidosis.
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Amiloidosis , Factores de Transcripción del Choque Térmico , Riñón , Ratones Noqueados , Respuesta de Proteína Desplegada , Animales , Amiloidosis/metabolismo , Amiloidosis/genética , Amiloidosis/patología , Factores de Transcripción del Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico/genética , Ratones , Riñón/patología , Riñón/metabolismo , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/genética , Modelos Animales de Enfermedad , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/genética , Enfermedades Renales/etiología , Ratones Endogámicos C57BLRESUMEN
Light chain amyloidosis is a conformational disease caused by the abnormal proliferation and deposition of antibody light chains as amyloid fibers in organs and tissues. The effect of Cu(II) binding to the model recombinant protein 6aJL2-R24G was previously characterized in our group, and we found an acceleration of the aggregation kinetics of the protein. In this study, in order to confirm the Cu(II) binding sites, histidine variants of 6aJL2-R24G were prepared and the effects of their interaction with Cu(II) were analyzed by circular dichroism, fluorescence spectroscopy, isothermal calorimetry titrations, and molecular dynamics simulations. Confirming our earlier work, we found that His8 and His99 are the highest affinity Cu(II) binding sites, and that Cu(II) binding to both sites is a cooperative event.
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Cobre , Histidina , Unión Proteica , Cobre/metabolismo , Cobre/química , Histidina/química , Histidina/metabolismo , Humanos , Sitios de Unión , Simulación de Dinámica Molecular , Cadenas Ligeras de Inmunoglobulina/metabolismo , Cadenas Ligeras de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/química , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/metabolismo , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis/metabolismo , Amiloidosis/genética , CinéticaRESUMEN
SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-ß (Aß) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Amiloidosis , Proteínas Proto-Oncogénicas , Transactivadores , Transcriptoma , Animales , Masculino , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Amiloidosis/genética , Amiloidosis/metabolismo , Amiloidosis/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Placa Amiloide/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Importance: Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy. Observations: Transthyretin (TTR) protein transports thyroxine (thyroid hormone) and retinol (vitamin A) and is synthesized predominantly by the liver. When the TTR protein misfolds, it can form amyloid fibrils that deposit in the heart causing heart failure, heart conduction block, or arrhythmia such as atrial fibrillation. The biological processes by which amyloid fibrils form are incompletely understood but are associated with aging and, in some patients, affected by inherited variants in the TTR genetic sequence. ATTR amyloidosis results from misfolded TTR protein deposition. ATTR can occur in association with normal TTR genetic sequence (wild-type ATTR) or with abnormal TTR genetic sequence (variant ATTR). Wild-type ATTR primarily manifests as cardiomyopathy while ATTR due to a genetic variant manifests as cardiomyopathy and/or polyneuropathy. Approximately 50â¯000 to 150â¯000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I), an allele with an origin in West African countries, that is present in 3.4% of African American individuals in the US or approximately 1.5 million persons. The diagnosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis. Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure. An ATTR-directed therapy that inhibited misfolding of the TTR protein (tafamidis, a protein stabilizer), compared with placebo, reduced mortality from 42.9% to 29.5%, reduced hospitalizations from 0.7/year to 0.48/year, and was most effective when administered early in disease course. Conclusions and Relevance: ATTR amyloidosis causes cardiomyopathy in up to approximately 150â¯000 people in the US and tafamidis is the only currently approved therapy. Tafamidis slowed progression of ATTR amyloidosis and improved survival and prevented hospitalization, compared with placebo, in people with ATTR-associated cardiomyopathy.
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Amiloidosis , Cardiomiopatías , Insuficiencia Cardíaca , Prealbúmina , Humanos , Amiloidosis/complicaciones , Amiloidosis/epidemiología , Amiloidosis/genética , Amiloidosis/metabolismo , Cardiomiopatías/etiología , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Prealbúmina/genética , Prealbúmina/metabolismo , Negro o Afroamericano/etnología , Negro o Afroamericano/genética , Negro o Afroamericano/estadística & datos numéricos , Estados Unidos/epidemiología , África Occidental , Pliegue de ProteínaAsunto(s)
Amiloidosis , Linfocitos B , Macroglobulinemia de Waldenström , Humanos , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/patología , Amiloidosis/genética , Amiloidosis/patología , Linfocitos B/patología , Linfocitos B/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age- and sex-related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild-type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6- to 14-month-old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age-related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aß40 and Aß42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female-biased manner.
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Enfermedad de Alzheimer , Amiloidosis , Disfunción Cognitiva , Animales , Femenino , Masculino , Ratones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidosis/patología , Amiloidosis/metabolismo , Amiloidosis/genética , Encéfalo/patología , Encéfalo/metabolismo , Disfunción Cognitiva/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Micronúcleos con Defecto Cromosómico , Presenilina-1/genética , Presenilina-1/metabolismo , Telómero/metabolismo , Telómero/genéticaRESUMEN
Renal amyloid-associated (AA) amyloidosis is a harmful complication of familial Mediterranean fever (FMF). Its occurrence involves polymorphisms and mutations in the Serum Amyloid A1 (SAA1) and Mediterranean Fever (MEFV) genes, respectively. In Algeria, the association between SAA1 variants and FMF-related amyloidosis was not investigated, hence the aim of this case-control study. It included 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis, and 21 without amyloidosis). All were genotyped for the SAA1 alleles (SAA1.1, SAA1.5, and SAA1.3), and a subset of them for the - 13 C/T polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were performed using Chi-square and Fisher tests. The SAA1.1/1.1 genotype was predominant in amyloid FMF patients, compared to non-amyloid FMF patients (p = 0.001) and controls (p < 0.0001). SAA1.1/1.5 was higher in non-amyloid patients (p = 0.0069) and in controls (p = 0.0082) than in patients with amyloidosis. Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1.1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119). The SAA1.1/1.5 genotype [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis. In all groups, the - 13 C/C genotype predominated, and was not related to renal complication [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915). In conclusion, in contrast to the - 13 C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population.
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Amiloidosis , Fiebre Mediterránea Familiar , Humanos , Fiebre Mediterránea Familiar/complicaciones , Fiebre Mediterránea Familiar/genética , Estudios de Casos y Controles , Amiloidosis/genética , Factores de Riesgo , Pirina , Proteína Amiloide A SéricaRESUMEN
PURPOSE: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. METHODS: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. RESULTS: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10- 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). CONCLUSIONS: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.
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Amiloidosis , Prealbúmina , Humanos , Prealbúmina/genética , Mutación , Amiloidosis/diagnóstico , Amiloidosis/genética , Fenotipo , Genética de PoblaciónRESUMEN
Amyloidosis is a rare cause of inherited kidney disease, with most variants responsible for prominent glomerular involvement. In this issue, Kmochová et al. reported the first description of autosomal dominant medullary amyloidosis due to apolipoprotein A4 variants, resulting in slowly progressive chronic kidney disease with minimal proteinuria. Combining next-generation sequencing with histopathological studies incorporating Congo red staining and mass spectrometry should be considered in the diagnostic workup of hereditary tubulointerstitial disorders not identified after routine genetic testing.
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Amiloidosis , Nefritis Intersticial , Insuficiencia Renal Crónica , Humanos , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/genética , Nefritis Intersticial/complicaciones , Amiloidosis/diagnóstico , Amiloidosis/genética , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/genética , Pruebas GenéticasRESUMEN
The mechanism that converts native human transthyretin into amyloid fibrils in vivo is still a debated and controversial issue. Commonly, non-physiological conditions of pH, temperature, or organic solvents are used in in vitro models of fibrillogenesis of globular proteins. Transthyretin amyloid formation can be achieved under physiological conditions through a mechano-enzymatic mechanism involving specific serine proteases such as trypsin or plasmin. Here, we investigate S52P and L111M transthyretin variants, both causing a severe form of systemic amyloidosis mostly targeting the heart at a relatively young age with heterogeneous phenotype among patients. Our studies on thermodynamics show that both proteins are significantly less stable than other amyloidogenic variants. However, despite a similar thermodynamic stability, L111M variant seems to have enhanced susceptibility to cleavage and a lower tendency to form fibrils than S52P in the presence of specific proteases and biomechanical forces. Heparin strongly enhances the fibrillogenic capacity of L111M transthyretin, but has no effect on the S52P variant. Fibrillar seeds similarly affect the fibrillogenesis of both proteins, with a stronger effect on the L111M variant. According to our model of mechano-enzymatic fibrillogenesis, both full-length and truncated monomers, released after the first cleavage, can enter into fibrillogenesis or degradation pathways. Our findings show that the kinetics of the two processes can be affected by several factors, such as intrinsic amyloidogenicity due to the specific mutations, environmental factors including heparin and fibrillar seeds that significantly accelerate the fibrillogenic pathway.
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Amiloidosis , Glicosaminoglicanos , Humanos , Prealbúmina/genética , Amiloidosis/genética , Amiloidosis/metabolismo , Amiloide/metabolismo , HeparinaRESUMEN
ABSTRACT: Familial Mediterranean fever (FMF) is an inherited, autoinflammatory disease with a high prevalence in Middle Eastern and Mediterranean populations including Turks, Iranian, Spanish, Sephardic Jews, Arabs, and other Mediterranean ethnic groups. Autoinflammatory diseases are genetically predetermined disorders with multisystem effects primarily caused by defects in innate immunity. Although primarily known for an autosomal recessive mode of inheritance, there are increasing case reports associated with single Mediterranean fever (MEFV) mutation or dominant transmission. There have been over 300 variants identified in the MEFV gene; however, roughly 9-11 variants are responsible for the phenotypical expression seen with FMF. Symptoms include recurrent episodes of fever of unknown origin, abdominal, chest, or joint pain because of serosal inflammation. Persistent elevations in serum amyloid A can lead to complications like renal amyloidosis, kidney dysfunction, and end-stage kidney disease. Familial Mediterranean fever is diagnosed clinically using the Tel-Hashomer criteria and confirmed through genetic testing. Treatment includes initiation of colchicine with the goal of stopping attacks and preventing renal dysfunction and end-stage kidney disease. Genetic testing helps to identify the specific mutation allowing the provider to create a patient-specific treatment plan, monitor for complications such as renal amyloidosis, and enhance knowledge on the genetic heterogeneity and possible epigenetic factors.
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Amiloidosis , Fiebre Mediterránea Familiar , Fallo Renal Crónico , Humanos , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/genética , Fiebre Mediterránea Familiar/complicaciones , Irán , Colchicina/uso terapéutico , Amiloidosis/genética , Amiloidosis/complicaciones , Mutación/genética , Fallo Renal Crónico/complicaciones , Pirina/genéticaRESUMEN
Amyloid resistance is the inability or the reduced susceptibility of an organism to develop amyloidosis. In this study we have analysed the molecular basis of the resistance to systemic AApoAII amyloidosis, which arises from the formation of amyloid fibrils from apolipoprotein A-II (ApoA-II). The disease affects humans and animals, including SAMR1C mice that express the C allele of ApoA-II protein, whereas other mouse strains are resistant to development of amyloidosis due to the expression of other ApoA-II alleles, such as ApoA-IIF. Using cryo-electron microscopy, molecular dynamics simulations and other methods, we have determined the structures of pathogenic AApoAII amyloid fibrils from SAMR1C mice and analysed the structural effects of ApoA-IIF-specific mutational changes. Our data show that these changes render ApoA-IIF incompatible with the specific fibril morphologies, with which ApoA-II protein can become pathogenic in vivo.