MEFV sequence variants and amyloidosis: still an enigmatic question

Altiok, Ozden; Séguret, Fabienne; Touitou, Isabelle

doi:10.1002/humu.10137

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…The main limitation of our study is that the role of the α/α genotype of the SAA1 gene for serum amyloid A1 was not addressed. SAA1 was recently identified as the first non‐ MEFV genetic risk factor for renal amyloidosis (10–12, 22, 23). The study of this gene was an impossible task under the current circumstances because SAA was not known as a risk factor at the time the project was created, and SAA genotyping and serum measures are not routinely performed.…”

Section: Discussionmentioning

confidence: 99%

Country as the primary risk factor for renal amyloidosis in familial mediterranean fever

Touitou¹,

Sarkisian²,

Medlej‐Hashim³

et al. 2007

Arthritis & Rheumatism

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244

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Objective. Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis.Methods. Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis).Results. Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified.Conclusion. Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.Familial Mediterranean fever (FMF) is the most frequent and the best understood hereditary periodic fever (1). When complete, the clinical picture reveals short episodes of fever, abdominal, thoracic, and joint pain, and erysipelas-like erythema.

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Section: Discussionmentioning

confidence: 99%

Country as the primary risk factor for renal amyloidosis in familial mediterranean fever

Touitou¹,

Sarkisian²,

Medlej‐Hashim³

et al. 2007

Arthritis & Rheumatism

Self Cite

244

141

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“…24). Some factors that appear to predispose to amyloidosis have been identified: the M694V mutation has been linked to severe disease and an increased risk of amyloidosis in some studies (25)(26)(27)(28)(29)(30)(31)(32) but not in others (33)(34)(35); the SAA1 gene haplotype is associated with up to 7-fold increased risk of amyloidosis (28,30,33,36), and male patients have as much as a 4-fold greater risk of amyloid deposition than do female patients (28,30,37). Although it is clear that amyloidosis is a common complication of FMF, it is also obvious that a multifactorial mechanism is at play.…”

Section: Discussionmentioning

confidence: 99%

Expression of ASC in Renal Tissues of Familial Mediterranean Fever Patients with Amyloidosis: Postulating a Role for ASC in AA Type Amyloid Deposition

Balcı-Peynircioğlu

Waite

Schaner

et al. 2008

Exp Biol Med (Maywood)

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Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis; in some cases, ensuing amyloidosis results in kidney damage. Treatment with colchicine reduces the frequency and severity of FMF attacks and prevents amyloidosis, although the mechanisms behind these effects are unknown. Pyrin, the protein product of the MEFV gene, interacts with ASC, a key molecule in apoptotic and inflammatory processes. ASC forms intracellular speck-like aggregates that presage cell death. Here we show that cell death after ASC speck formation is much slower in nonmyeloid cells than in myeloid cells. Additionally, we demonstrate that colchicine prevents speck formation and show that specks can survive in the extracellular space after cell death. Because we also found that ASC is expressed in renal glomeruli of patients with FMF but not in those of control patients, we posit that high local ASC expression may result in speck formation and that specks from dying cells may persist in the extracellular space where they have the potential (perhaps in association with pyrin) to nucleate amyloid. The fact that speck formation requires an intact microtubule network as shown here could potentially account for the ability of prophylactic colchicine to prevent or reverse amyloidosis in patients with FMF.

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“…Patients with a 1.1/1.1 genotype have a three-to sevenfold increased risk for amyloidosis [27,28,29,30].…”

Section: Factors Influencing the Risk Of Type Aa Amyloidosis Polymorpmentioning

confidence: 99%

Recent Insights into the Pathogenesis of Type AA Amyloidosis

Hilst

2011

The Scientific World JOURNAL

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The amyloidoses are a group of life-threatening diseases in which fibrils made of misfolded proteins are deposited in organs and tissues. The fibrils are stable, insoluble aggregates of precursor proteins that have adopted an antiparallel β-sheet structure. In type AA, or reactive, amyloidosis, the precursor protein of the fibrils is serum amyloid A (SAA). SAA is a 104-amino-acid protein that is produced in the liver in response to proinflammatory cytokines. Although the protein that is produced by the liver contains 104 amino acids, only the N-terminal 66–76 amino acids are found in amyloid fibrils. Furthermore, SAA has been shown to have an α-helical structure primarily. Thus, for SAA to be incorporated into an amyloid fibril, two processes have to occur: C-terminal cleavage and conversion into a β-sheet. Only a minority of patients with elevated SAA levels develop amyloidosis. Factors that contribute to the risk of amyloidosis include the duration and degree of SAA elevation, polymorphisms in SAA, and the type of autoinflammatory syndrome. In the Hyper-IgD syndrome, amyloidosis is less prevalent than in the other autoinflammatory diseases. In vitro work has shown that the isoprenoid pathway influences amyloidogenesis by farnesylated proteins. Although many proteins contain domains that have a potential for self-aggregation, amyloidosis is only a very rare event. Heat shock proteins (HSPs) are chaperones that assist other proteins to attain, maintain, and regain a functional conformation. In this review, recent insights into the pathogenesis of amyloidosis are discussed, in addition to a new hypothesis for a role of HSPs in the pathogenesis of type AA.

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MEFV sequence variants and amyloidosis: still an enigmatic question

Cited by 7 publications

References 15 publications

Country as the primary risk factor for renal amyloidosis in familial mediterranean fever

Country as the primary risk factor for renal amyloidosis in familial mediterranean fever

Expression of ASC in Renal Tissues of Familial Mediterranean Fever Patients with Amyloidosis: Postulating a Role for ASC in AA Type Amyloid Deposition

Recent Insights into the Pathogenesis of Type AA Amyloidosis

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