6 results on '"Lemos, Carolina"'
Search Results
2. Beyond Val30Met transthyretin (TTR): variants associated with age-at-onset in hereditary ATTRv amyloidosis.
- Author
-
Alves-Ferreira, Miguel, Azevedo, Ana, Coelho, Teresa, Santos, Diana, Sequeiros, Jorge, Alonso, Isabel, Sousa, Alda, and Lemos, Carolina
- Subjects
CARDIAC amyloidosis ,TRANSTHYRETIN ,AMYLOIDOSIS ,GENETIC regulation ,TANDEM repeats ,PROMOTERS (Genetics) - Abstract
V30M in transthyretin (TTR) gene is causative for hereditary ATTRv amyloidosis (familial amyloid polyneuropathy). ATTRv amyloidosis shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We aim at identifying genetic modifiers of disease onset that may contribute to this variability in Portuguese patients by identifying other variants in TTR locus, beyond the ATTRv amyloidosis causing variant that could play a regulatory role in its expression level. We analysed DNA samples of 330 ATTRV30M carriers (299 patients, 31 aged-asymptomatic carriers aged >40 years) from 120 families currently under follow-up. A generalised estimating equation analysis (GEE) was used to take into account non-independency of AO between relatives. An intensive in silico analysis was performed in order to understand a possible regulation of gene expression. We found 11 rare variants in the promoter, coding and intron/exon boundaries of the TTR gene associated with the onset of symptoms before and after age 40 years, namely 2 novel ones and a tandem CA-dinucleotide repeat. Furthermore, of the 4 common variants found, one was significantly associated with AO and may influence the constitutive splicing of TTR pre-mRNA. The seven ATTRV30M/V30M homozygous do not carry any of the variants identified in this study, including the common ones. In silico analysis disclosed significant alterations in the mechanism of splicing, transcription factors and miRNAs binding. Variants within the promoter region may modify disease expressivity and variants in the 3'UTR can impact the efficacy of novel therapeutic interventions. Importantly, the putative mechanisms of regulation of gene expression within the TTR gene deserve to be better explored, in order to be used in the future as potential therapeutical targets. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. Large normal alleles of ATXN2 decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met patients.
- Author
-
Santos, Diana, Coelho, Teresa, Alves‐Ferreira, Miguel, Sequeiros, Jorge, Mendonça, Denisa, Alonso, Isabel, Sousa, Alda, Lemos, Carolina, and Alves-Ferreira, Miguel
- Subjects
TRANSTHYRETIN ,AGE of onset ,ALLELES ,NEUROLOGICAL disorders ,OLIGONUCLEOTIDES ,POLYMERASE chain reaction - Abstract
Objective: Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age at onset (AO) ranges from 19 to 82 years, and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of 10 genes had a possible modifier effect in AO in Portuguese TTR-FAP Val30Met families.Methods: We analyzed 329 Portuguese patients from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK) was assessed by single and multiplex polymerase chain reaction, using fluorescently labeled primers, followed by capillary electrophoresis. We used a family-centered approach, and generalized estimating equations were used to account for AO correlation between family members.Results: For ATXN2, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR-FAP Val30Met, decreasing mean AO by 6 years (95% confidence interval = -8.81 to -2.19, p = 0.001). No association was found for the remaining repeat loci.Interpretation: Length of normal repeats at ATXN2 may modify AO in TTR-FAP Val30Met and may function as a risk factor. This can be due to the role of ATXN2 in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow-up of presymptomatic carriers. ANN NEUROL 2019;85:251-258. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
4. Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans.
- Author
-
Madhivanan, Kayalvizhi, Greiner, Erin R., Alves-Ferreira, Miguel, Soriano-Castell, David, Rouzbeh, Nirvan, Aguirre, Carlos A., Paulsson, Johan F., Chapman, Justin, Xin Jiang, Ooi, Felicia K., Lemos, Carolina, Dillin, Andrew, Prahlad, Veena, Kelly, Jeffery W., and Encalada, Sandra E.
- Subjects
CAENORHABDITIS elegans ,NEURODEGENERATION ,NEUROTOXICOLOGY ,MUSCLES ,TRANSTHYRETIN - Abstract
Cell-autonomous and cell-nonautonomous mechanisms of neurodegeneration appear to occur in the proteinopathies, including Alzheimer's and Parkinson's diseases. However, how neuronal toxicity is generated from misfolding-prone proteins secreted by nonneuronal tissues and whether modulating protein aggregate levels at distal locales affects the degeneration of postmitotic neurons remains unknown. We generated and characterized animal models of the transthyretin (TTR) amyloidoses that faithfully recapitulate cell-nonautonomous neuronal proteotoxicity by expressing human TTR in the Caenorhabditis elegans muscle. We identified sensory neurons with affected morphological and behavioral nociception-sensing impairments. Nonnative TTR oligomer load and neurotoxicity increased following inhibition of TTR degradation in distal macrophage-like nonaffected cells. Moreover, reducing TTR levels by RNAi or by kinetically stabilizing natively folded TTR pharmacologically decreased TTR aggregate load and attenuated neuronal dysfunction. These findings reveal a critical role for in trans modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
5. Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases.
- Author
-
Beirão, João Melo, Malheiro, Jorge, Lemos, Carolina, Beirão, Idalina, Costa, Paulo, and Torres, Paulo
- Subjects
TRANSTHYRETIN ,AMYLOIDOSIS ,LIVER transplantation ,IRIS surgery ,PROTEINS ,GLAUCOMA diagnosis - Abstract
Purpose: Assessment of ocular involvement in transthyretin-related familial amyloidosis with polyneuropathy (FAP) in a large cohort of Portuguese patients. Methods: We reviewed the medical records of 513 Portuguese FAP mutation carriers, at the Ophthalmology Service, Centro Hospitalar do Porto, between 1 January 2008 and 31 January 2013. Abnormal conjunctiva vessels (ACV), Schirmer test, tear break-up time (TBUT), amyloid deposition on the iris (DAI), scalloped iris, amyloid deposition on the anterior capsule of the lens (DAL), vitreous amyloidosis, retinal amyloid angiopathy and glaucoma were evaluated and registered. Results: Of the 513 carriers, 477 (93%) had clinical systemic disease with a median duration of 9.3 (5.1-13.7) years and 247 were men. Of these, 343 (72%) had been liver transplanted, on median of 6.6 (3.3-10.8) years before inclusion in this study. No ocular abnormalities were identified in the asymptomatic carriers (7%). The abnormalities observed with decreasing frequency were abnormal TBUT (379 patients, 79.5%, 751 eyes), abnormal Schirmer test (320 patients, 67%, 635 eyes), DAI (183 patients, 38.4%, 350 eyes), DAL (157 patients, 32.9%, 308 eyes), scalloped iris (133 patients, 27.9%, 238 eyes), glaucoma (97 patients, 20%, 165 eyes), vitreous amyloidosis (83 patients, 17.4%, 139 eyes), ACV (68 patients, 14%, 136 eyes) and amyloidotic retinal angiopathy (21 patients, 4%, 32 eyes). Patients with abnormal Schirmer test ( p < 0.001), scalloped iris ( p = 0.006) and vitreous amyloidosis ( p = 0.007) were significantly older than the others. According to their age of onset of systemic disease, the patients have been split into early-onset (<40 years old), intermediate-onset (40-50 years old), late onset (>50 years old) and asymptomatic carriers. We observed a statistically significant difference in the prevalence of ACV ( p = 0.045) and of an abnormal Schirmer test ( p = 0.004) between groups. Transplanted patients have a significantly higher prevalence of DAI ( p = 0.001), DAL ( p = 0.009) and vitreous amyloidosis ( p = 0.025) than non-transplanted patients. Of the 165 eyes with glaucoma, 92.1% had scalloped iris ( p < 0.001) and of 32 eyes with retinal amyloidotic angiopathy, 68.8% had vitreous amyloidosis ( p < 0.001). All prevalences increased with time of disease. The earliest ocular manifestations were abnormal Schirmer test and abnormal TBUT (12% and 17% at 5 years of clinical disease) and the least prevalent was retinal amyloid angiopathy (8% at 15 years of clinical disease). Conclusion: Ocular disorders in FAP patients are common, and their prevalence increases with disease duration. Prevalence is influenced by several factors, such as the age at onset of FAP and liver transplantation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
6. Impact of liver transplantation on the natural history of oculopathy in Portuguese patients with transthyretin (V30M) amyloidosis.
- Author
-
Beirão, João Melo, Malheiro, Jorge, Lemos, Carolina, Matos, Eduarda, Beirão, Idalina, Pinho-Costa, Paulo, and Torres, Paulo
- Subjects
LIVER transplantation ,TRANSTHYRETIN ,AMYLOIDOSIS ,PROTEIN metabolism disorders ,PROTEINS - Abstract
Purpose: Evaluation of the impact of liver transplantation in the natural history of ocular disorders in familial amyloidotic polyneuropathy (FAP) amyloidosis TTR V30M related (ATTR V30M) patients. Design: A clinical, retrospective and cross-sectional study of 64 Portuguese FAP ATTR V30M patients was carried out between January 2005 and December 2011. Methods: Thirty-two liver transplanted patients (both eyes) aged 39.6-53.8 years old, 32/32 male/female, were paired with an equal number of non-transplanted patients, matching for age, gender, age at onset, disease duration and gender of transmitting parent. Intervention or observation procedure: Routine ophthalmological observation. Main outcome measures: Slit-lamp observation for abnormal conjunctival vessels (ACV), tears break-up time, iris, lens; fundus observation for vitreous, retina and optic disc; Schirmer test. Results: Liver transplantation had no influence on tears break-up time, deposition of amyloid on the iris and retinal amyloid angiopathy. Slight, non-statistically significant protective effects of liver transplantation were noted in the first years for some ocular manifestations (ACV and scalloped iris), except for the abnormal Schirmer test, which was significantly more prevalent in non-transplanted patients' eyes (81% versus 56%, p = 0.002). On the other hand, deposition of amyloid on the lens, vitreous amyloidosis and glaucoma were apparently more common in transplanted patients. Those differences tended to disappear with time. Conclusions: Ocular manifestations of FAP were not influenced by liver transplantation in a meaningful way. Both transplanted and non-transplanted FAP patients need similar regular follow-up due to long-term risk of serious ocular disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.