Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30.

J Med Genet. 1999 Aug;36(8):629-32. Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30. Munar-Qués M, Pedrosa JL, Coelho T, Gusmão L, Seruca R, Amorim A, Sequeiros J. Grupo de Estudio de la PAF, Palma de Mallorca, Spain. Abstract Twin studies are an important tool in medical genetics for the evaluation of the relative roles of genetic and non-genetic factors in several diseases. Familial amyloidotic polyneuropathy type I (FAP-I), TTR Met 30, was present in two sets of proven monozygotic (MZ) twins, one from Majorca and the other from Portugal. Monozygosity was established by analysis of DNA polymorphisms. Both pairs were discordant for age at onset and some clinical manifestations of FAP-I. We reviewed the differences in age at onset and clinical features in both sets and in two other pairs of presumed MZ twins with FAP-I and compared them with those in MZ twin pairs with other Mendelian disorders, such as neurofibromatosis type 1, Huntington's disease, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. We conclude that, in addition to the postulated modifying genes, there must be a significant contribution from non-genetic factors to the phenotypic variability of FAP-I (age at onset and clinical expression), either because of environmental differences or stochastic events during (or after) the twinning process. PMID: 10465115 [PubMed - indexed for MEDLINE]PMCID: PMC176297

Beyond Genetic Factors in Familial Amyloidotic Polyneuropathy: Protein Glycation and the Loss of Fibrinogen's Chaperone Activity

Familial amyloidotic polyneuropathy (FAP) is a systemic conformational disease characterized by extracellular amyloid fibril formation from plasma transthyretin (TTR). This is a crippling, fatal disease for which liver transplantation is the only effective therapy. More than 80 TTR point mutations are associated with amyloidotic diseases and the most widely accepted disease model relates TTR tetramer instability with TTR point mutations. However, this model fails to explain two observations. First, native TTR also forms amyloid in systemic senile amyloidosis, a geriatric disease. Second, age at disease onset varies by decades for patients bearing the same mutation and some mutation carrier individuals are asymptomatic throughout their lives. Hence, mutations only accelerate the process and non-genetic factors must play a key role in the molecular mechanisms of disease. One of these factors is protein glycation, previously associated with conformational diseases like Alzheimer's and Parkinson's. The glycation hypothesis in FAP is supported by our previous discovery of methylglyoxal-derived glycation of amyloid fibrils in FAP patients. Here we show that plasma proteins are differentially glycated by methylglyoxal in FAP patients and that fibrinogen is the main glycation target. Moreover, we also found that fibrinogen interacts with TTR in plasma. Fibrinogen has chaperone activity which is compromised upon glycation by methylglyoxal. Hence, we propose that methylglyoxal glycation hampers the chaperone activity of fibrinogen, rendering TTR more prone to aggregation, amyloid formation and ultimately, disease

Nanotools for Megaproblems: Probing Protein Misfolding Diseases Using Nanomedicine M

Misfolding and self-assembly of proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primary nanofilaments, nanorings, filaments, protofibrils, fibrils, etc.) is a common theme unifying a number of human pathologies termed protein misfolding diseases. Recent studies highlight increasing recognition of the public health importance of protein misfolding diseases, including various neurodegenerative disorders and amyloidoses. It is understood now that the first essential elements in the vast majority of neurodegenerative processes are misfolded and aggregated proteins. Altogether, the accumulation of abnormal protein nanoensembles exerts toxicity by disrupting intracellular transport, overwhelming protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a major problem in the production of recombinant therapeutic proteins. Formulation of these therapeutic proteins into delivery systems and their in vivo delivery are often complicated by protein association. Thus, protein folding abnormalities and subsequent events underlie a multitude of human pathologies and difficulties with protein therapeutic applications. The field of medicine therefore can be greatly advanced by establishing a fundamental understanding of key factors leading to misfolding and self-assembly responsible for various protein folding pathologies. This article overviews protein misfolding diseases and outlines some novel and advanced nanotechnologies, including nanoimaging techniques, nanotoolboxes and nanocontainers, complemented by appropriate ensemble techniques, all focused on the ultimate goal to establish etiology and to diagnose, prevent, and cure these devastating disorders