Transthyretin

Background: Transthyretin (TTR) aggregation is associated with systemic amyloidosis. Results: Residue replacements on the F and H strands hinder TTR aggregation. Conclusion: The F and H strands are aggregation-driving segments of TTR. The binding of designed peptides inhibits protein aggregation. Significance: We point the way to new therapeutic approaches against TTR aggregation by using peptides to block amyloid segments.

Transthyretin (TTR), a carrier protein for thyroxine and retinol in plasma and cerebrospinal fluid (CSF), has been shown to bind the amyloid beta peptide. Accordingly, TTR has been suggested to protect against amyloid beta deposition, a key pathological feature in Alzheimer's disease (AD). Supporting this view are the reduced TTR levels found in CSF of patients with AD, as well as reports of altered TTR expression in the cortex and hippocampus of AD rodent models. Importantly, early characterization of TTR distribution revealed the choroid plexus as the site of TTR synthesis within the brain. To resolve this controversy we used precise laser microdissection technology to assay for TTR mRNA expression. Our results clearly demonstrate that TTR is not produced in the brain parenchyma of wild-type mice nor in two different transgenic mouse models of AD, suggesting that contamination by choroid plexus contributed to the recent results indicating TTR production in various brain regions. The relevance of TTR to AD should now take into consideration TTR production by the choroid plexus and its ability, in the CSF, to sequester the amyloid beta peptide.

A new TTR variant, Val122Ala, was characterized in an individual who carried the Gly6Ser polymorphism on the opposite allele. The main clinical feature of this familial transthyretin amyloidosis (ATTR) variant is extensive cardiomyopathy. The detection and characterization of the variant were performed using a combination of isoelectric focusing (IEF), restriction fragment length polymorphism (RFLP), immunoprecipitation, electrospray ionization mass spectrometry (ESIMS), HPLC (high performance liquid chromatography)/ESIMS, and matrix-assisted laser desorption/ionization mass spectrometry (MALDIMS). The results were confirmed by DNA analysis. The propositus has a brother who carries the new variant but not the polymorphism.

Primary (AL) amyloidosis is the most prevalent type of systemic amyloidosis, and management of this disease has evolved through the years from supportive care to aggressive treatments that include immunomodulatory agents and high-dose chemotherapy with hematopoietic stem cell transplantation. However, other types of amyloidosis are increasingly recognized, such as familial amyloidosis and senile cardiac amyloidosis, and management of these conditions is different from that of AL amyloidosis. Congo red staining with exhibition of an apple-green birefringence is diagnostic of amyloid. Immunohistochemistry can detect amyloid deposits but has limitations, and newer molecular techniques such as mass spectrometry show promise in determining types of amyloidosis. Physicians need to be aware of clinical scenarios that can mimic AL amyloidosis to avoid misdiagnosis and harm to the patient.

El diagnostico nutricional de ninos mediante indicadores antropometricos tales como, peso para la edad (P-E), peso para la talla (P-T) y talla para la edad (T-E), permite conocer su condicion nutricional. No obstante dichos indicadores carecen de la agudeza para diagnosticar cuando el proceso de desnutricion esta en sus comienzos. El objetivo de este trabajo fue investigar las proteinas plasmaticas de fase aguda: transtirretina (TTR), proteina ligadora de retinol (RBP) y transferrina como posibles indicadores bioquimicos en los casos de deficit nutricional en ninos en edad escolar. La evaluacion antropometrica se realizo mediante los indicadores de crecimiento bidimensional y de composicion corporal (OMS y EVANUT: Evanut toma como referencia los datos nacionales propuestos por FUNDACREDESA). Se tomaron alicuotas de plasma sanguineo para evaluar a TTR por inmunodifusion radial y turbidimetria, RBP por ELISA y transferrina por turbidimetria. Los indicadores antropometricos de las pobl...

... prediction and test of a mutational "hot-spot" on the transthyretin molecule associated with FAP amyloidogenesis Louise C. Serpell', Gundars Goldsteins', Ingrid Dacklin2, Erik Lzindgren2 and Colin CF Blake' ... accuinulate six mutations be-tween thein. ...

Senile systemic amyloidosis (SSA) results from deposition, predominantly in the heart, of amyloid fibrils derived from wild-type transthyretin (T TR) molecules. Cardiac autopsies indicate that SSA progressively increases in subjects 80 years of age and older. However, only a few cases of patients with SSA and cardiac failure have been recognized by cardiac biopsies during life. Here, we report a case of heart transplantation in a 68-year-old male patient with SSA. After cardiopulmonary resuscitation in October 1998, he underwent complete evaluation. Myocardial biopsies revealed the presence of amyloid deposition. Immunohistochemical staining of the amyloid indicated T TR. Genomic DNA analysis of the T TR exons did not result in any identification of a mutation. In 2001, heart transplantation was performed because progressive heart failure occurred. At the 1-year follow-up, no amyloid deposits were found in the donor heart. At the 2-year follow-up, the patient's physical and mental health was excellent. We conclude that heart transplantation can be an effective treatment in progressive heart failure due to SSA.