Screening and biochemical characterization of transthyretin variants in the Portuguese population

Alves, Isabel; Altland, Klaus; Almeida, Maria Rosário; Winter, Pia; Saraiva, Maria João

doi:10.1002/(sici)1098-1004(1997)9:3<226::aid-humu3>3.3.co;2-w

Cited by 15 publications

(25 citation statements)

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“…The TTR Thr119Met variant has previously been described to be more stable than TTR wt [27,28]. TTR Thr119Met has also been shown to protect individuals carrying the TTR Val30Met mutation from developing FAP [29]. An increased stability decreases the probability of TTR to form cytotoxic species, making the TTR Thr119Met variant a possible negative control.…”

Section: The Cytotoxic Effect Of Ttr On Sh-sy5y Cells Is Ttr Specificmentioning

confidence: 99%

Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form

Lindhagen-Persson

Vestling

Reixach

et al. 2008

Amyloid

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Familial amyloidotic polyneuropathy (FAP) is linked to destabilising point mutations in the human plasma protein transthyretin (TTR). Consistent with similar amyloid disorders, low molecular weight TTR oligomers have been shown to exert the major cytotoxic effect. The amyloid structure of TTR contains non-native inter-molecular disulphide linkages via the cysteine at position 10 (Cys10). Moreover, substitution of Cys10 in a mouse model for TTR-amyloidosis abolishes TTR deposits, indicating an important role of Cys10 in FAP pathogenesis. However, the role of disulphide bridges in TTR cytotoxicity has not been elucidated. By probing Cys10Ser TTR variants to the human neuroblastoma SH-SY5Y cell line, we have addressed this question, and our results clearly show that formation of an inter-molecular disulphide bridge is not a pre-requisite for TTR cytotoxicity. This finding suggests that prevention of inter-molecular TTR disulphide bridges as a therapeutic intervention will not impair the cytotoxic potential of TTR.

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Section: The Cytotoxic Effect Of Ttr On Sh-sy5y Cells Is Ttr Specificmentioning

confidence: 99%

Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form

Lindhagen-Persson

Vestling

Reixach

et al. 2008

Amyloid

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“…[Met1 19lTTR has been described as a non-amyloidogenic TTR variant in several populations (Harrison et al, 1991 ;Ii et al, 1992;Alves et al, 1997).…”

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confidence: 99%

“…[Met119]TTR carriers have been shown to present higher plasma TTR levels (Harrison et al, 1991;Alves et al, 1993) although within normal limits, in contrast with FAP patients, carriers of [Met30]TTR whose TTR concentrations are lower than normal (Saraiva et al, 1983 (Alves et al, 1997). In these latter individuals, the evolution of the disease seems to be more benign than in typical [Met30]TTR carriers (Coelho et al, 1993(Coelho et al, , 1996 (Coelho et al, 1996).…”

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confidence: 99%

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Comparative Stability and Clearance of [Met30]Transthyretin and [Met119]Transthyretin

Alves

Hays

Saraiva

1997

European Journal of Biochemistry

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[Metl19]Transthyretin has been described as a non-amyloidogenic transthyretin variant. In Portugal, it has also been found in compound heterozygotic individual carriers of [Met30]transthyretin, the most prevalent variant associated with familial amyloidotic polyneuropathy. In these individuals, the evolution of the disease seems to be more benign than in typical [Met3O]transthyretin carriers, suggesting a protective effect of [Metl19]transthyretin on the pathogenic effects of [Met30]transthyretin. To study the mechanisms of this protective effect, we performed comparative in vivo clearance studies. Heterotetrameric [Metl19]transthyretin showed a slower clearance, whereas homotetrameric [Met30]transthyretin presented a faster clearance. These data correlate with the relative TTR levels present in carriers of these mutations. Comparative analyses of the resistance to dissociation into monomers of serum transthyretin by 4M urea isoelectric focusing suggested a higher tetrameric stability of transthyretin in [Metl19]transthyretin carriers, in contrast to a lower stability in [Met30ltransthyretin carriers. The compound heterozygotes presented a pattern similar to the normal individuals. Our results suggest that the protective clinical effect of the Met1 19 mutation possibly involves the stabilisation of the tetrameric structure of transthyretin. Whether this behaviour correlates with the different metabolism found for the two variants is not known. The approaches reported here open some possibilities for the study and development of future therapeutic agents of familial amyloidotic polyneuropathy.

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“…Einzelne TTRMutationen sind apathogen [12]. Sie kommen als neutrale Polymorphismen teilweise in hoher Frequenz bei der weißen Bevölkerung vor [6] und können, wenn sie mit einem pathogenen Allel kombiniert sind, dessen Pathogenität abschwächen oder aufheben [2,28].…”

Section: Punktmutationen Erhöhen Die Amyloidogenität Von Ttrunclassified

Transthyretinassoziierte hereditäre Amyloidosen

et al. 2002

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Hereditary amyloidoses form a clinically and genetically heterogeneous group of autosomal-dominantly inherited diseases characterized by the ubiquitous extracellular deposit of fibrillary aggregated proteins. Main components of these unsolvable deposits are physiologic proteins that became amyloidogenic through genetically determined conformation changes resulting in an increase in beta-sheet structures. In the vast majority of cases, the offending protein is variant transthyretin (TTR), of which over 80 mutations are known. Among these, substitution of valine by methionine in position 30 (TTR-Met30) is the most commonly encountered. In typical cases, TTR amyloidoses present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Rarely, involvement of the leptomeningeal or meningovascular structures dominates the clinical picture. The clinical expression is highly variable, with many atypical manifestations. Asymptomatic mutations have recently been identified. The age of onset varies greatly between early adulthood and old age. Late-onset atypical manifestations and occurrence of asymptomatic carriers render identification of affected family members difficult despite autosomal-dominant inheritance. Orthotopic liver transplantation (OLT) is the only effective therapy available today. This OLT stops progression of the disease, which is otherwise invariably fatal, by removal of the main production site of the amyloidogenic protein. However, cardiac involvement may progress after OLT for unknown reasons. The indication for OLT and its success depend on the grade of cardiovascular and autonomic dysfunction at the time of surgery, age, comorbidity, and type of mutation. Alternative treatment modalities with drugs stabilizing the native tetrameric conformation of TTR, inhibiting fibril formation or breaking beta-sheet structures, are currently being intensively studied.

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Screening and biochemical characterization of transthyretin variants in the Portuguese population

Cited by 15 publications

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Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form

Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form

Comparative Stability and Clearance of [Met30]Transthyretin and [Met119]Transthyretin

Transthyretinassoziierte hereditäre Amyloidosen

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