Monoallelic expression of the TTR gene as a contributor to the age at onset and penetrance of TTR-related amyloidosis

Yordanova, Iglika; Pavlova, Z V; Kirov, Andrey; Todorov, Tihomir; Alexiev, A.; Sarafov, Stayko; Mateva, Lyudmila; Chamova, Teodora; Господинова, Мариана; Mitev, Vanio; Tournev, Ivailo; Тодорова, Албена

doi:10.1016/j.gene.2019.04.030

Cited by 5 publications

(6 citation statements)

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“…The differences in organ and tissue involvement in the context of the same TTR variant imply the influence of other genetic and epigenetic factors upon the clinical manifestation. There are various studies proposing the effect of non-coding cis-and trans-acting regulatory genetic factors on the TTR expression and tissue-specific amyloid formation, as well as the age at disease onset (35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Seven Years of Selective Genetic Screening Program and Follow-Up of Asymptomatic Carriers With Hereditary Transthyretin Amyloidosis in Bulgaria

Chamova¹,

Господинова

Asenov³

et al. 2022

Front. Neurol.

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Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, autosomal-dominant (AD) multisystem disorder resulting from the extracellular deposition of amyloid fibrils formed by a destabilized mutant form of transthyretin (TTR), a transport protein predominantly produced by the liver.AimThe aims of the current study are to demonstrate the Bulgarian experience with the screening programs among the high-risk patient population over the last 7 years, to present the results from the therapy with TTR stabilizer in our cohort, as well as to stress on the importance of a follow-up of asymptomatic carriers with TTR pathogenic variants by a multidisciplinary team of specialists.Materials and MethodsIn 2014, a screening program among the high-risk patient population for ATTRv was initiated in Bulgaria. On one hand, it was conducted to identify new patients and families among people with “red flag” clinical features, while on the other hand, the program aimed to identify TTR mutation carriers among the families with already genetically proven diagnoses. Sanger sequencing methodology was used to make fast target testing for mutations in the TTR gene in the suspected individuals. All of the identified carriers underwent subsequent evaluation for neurological, cardiac, gastroenterological, and neuro-ophthalmological involvement. Those considered affected were provided with multidisciplinary treatment and a follow-up.ResultsAs a result of a 7-year selective screening program among the high-risk patient population and relatives of genetically verified affected individuals, 340 carriers of TTR mutations were identified in Bulgaria with the following gene defects: 78.53% with Glu89Gln, 10.29% with Val30Met, 8.24% with Ser77Phe, 2.06% with Gly47Glu, and 0.59% with Ser52Pro. All of these affected displayed a mixed phenotype with variable ages at onset and rate of progression, according to their mutation. From the 150 patients treated with TTR stabilizer, 84 remained stable, while in other 66 patients the treatment was terminated either because of polyneuropathy progression or due to death. A program for a regular follow-up of asymptomatic carriers in the last 3 years enabled us to detect the transition of 39/65 to symptomatic patients and to initiate treatment in a timely manner.ConclusionBulgarian ATTRv patients display a mixed phenotype with some clinical peculiarities for each mutation that should be considered when treating the affected and the follow-up of the asymptomatic carriers of a specific gene defect.

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Section: Discussionmentioning

confidence: 99%

Seven Years of Selective Genetic Screening Program and Follow-Up of Asymptomatic Carriers With Hereditary Transthyretin Amyloidosis in Bulgaria

Chamova¹,

Господинова

Asenov³

et al. 2022

Front. Neurol.

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“…From the processed samples, 87% showed monoallelic expression and 13% biallelic expression in plasma, while in urine 58% showed monoallelic expression and 42% biallelic expression. Furthermore, it was observed that, at an early age, there is a predominant expression of the wild-type form, while the expression of the mutated allele increases with advancing age; when the onset of the disease is around the age of 50, it is possible that there is a biallelic expression, until there is some sort of natural selection or suppression, which favors the expression of the mutated transcripts [ 59 ].…”

Section: First Case Report Of Somatic Mosaicism In Hattr Patients And...mentioning

confidence: 99%

“…Patients with the missense mutation G>C, responsible for the amino acid substitution p.Glu89Gln, in the DNA extracted from blood but not in DNA extracted from buccal or hair bulb cells, have manifested the disease. These patients have not had transcriptional analysis of the TTR gene [ 14 , 59 , 60 ]. However, the involvement of other unidentified genes in the modulation of TTR gene expression is very likely.…”

Section: First Case Report Of Somatic Mosaicism In Hattr Patients And...mentioning

confidence: 99%

Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy

et al. 2022

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Point mutations of the transthyretin (TTR) gene are related with hereditary amyloidosis (hATTR). The number of people affected by this rare disease is only partially estimated. The real impact of somatic mosaicism and other genetic factors on expressivity, complexity, progression, and transmission of the disease should be better investigated. The relevance of this rare disease is increasing and many efforts have been made to improve the time to diagnosis and to estimate the real number of cases in endemic and non-endemic areas. In this context, somatic mosaicism should be better investigated to explain the complexity of the heterogeneity of the hATTR clinical features, to better estimate the number of new cases, and to focus on early and personalized gene therapy. Gene therapy can potentially improve the living conditions of affected individuals and is one of the central goals in research on amyloidosis related to the TTR gene, with the advantage of overcoming liver transplantation as the sole treatment for hATTR disease.

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“…We further anticipated that due to the large number and low penetrance of pathogenic TTR, single case reports of asymptomatic patients can be potentially misleading. [8][9][10] Thus, VUS of TTR that were reported in single patients or in one family were selected and assessed additionally.…”

Section: Introductionmentioning

confidence: 99%

“…As proof of principle, these in vitro tests were applied to TTR‐Ala65Val, a variant that was observed in a family with peripheral neuropathy. We further anticipated that due to the large number and low penetrance of pathogenic TTR, single case reports of asymptomatic patients can be potentially misleading 8‐10 . Thus, VUS of TTR that were reported in single patients or in one family were selected and assessed additionally.…”

Section: Introductionmentioning

confidence: 99%

Amyloidogenicity assessment of transthyretin gene variants

Grether

Napravnik

Imhof

et al. 2022

Ann Clin Transl Neurol

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Objective Hereditary transthyretin‐mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin‐gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non‐pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in vitro approach. Methods Thioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt‐transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in vitro. As proof of principle, the assays were applied to transthyretin‐Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants. Results Transthyretin‐Ala65Val showed a significantly higher amyloidogenic potential than wt‐transthyretin, in both turbidity‐ and Thioflavin T‐assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions. Interpretation We propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin‐Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity.

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Monoallelic expression of the TTR gene as a contributor to the age at onset and penetrance of TTR-related amyloidosis

Cited by 5 publications

References 20 publications

Seven Years of Selective Genetic Screening Program and Follow-Up of Asymptomatic Carriers With Hereditary Transthyretin Amyloidosis in Bulgaria

Seven Years of Selective Genetic Screening Program and Follow-Up of Asymptomatic Carriers With Hereditary Transthyretin Amyloidosis in Bulgaria

Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy

Amyloidogenicity assessment of transthyretin gene variants

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