Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met

Dardiotis, Efthimios; Koutsou, Pantelitsa; Zamba‐Papanicolaou, Eleni; Vonta, Filia; Hadjivassiliou, Marilena; Hadjigeorgiou, Georgios M.; Cariolou, Marios A.; Christodoulou, Kyproula; Kyriakides, Theodoros

doi:10.1016/j.jns.2009.05.018

Cited by 35 publications

(34 citation statements)

References 37 publications

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“…In Portugal and Japan, disease caused by the ATTR V30M variant usually develops between the third and fourth decades of life. Complement factor C1Q polymorphisms may modulate the age of onset and explain genetic anticipation with amyloid deposition at an earlier age in successive generations (24). In monozygotic twins from Spain, different ages of onset and phenotypes, including dissimilar kidney involvement, have been reported (25).…”

Section: Clinical Presentationmentioning

confidence: 99%

Transthyretin Amyloidosis and the Kidney

Lobato

Rocha

2012

Clinical Journal of the American Society of Nephrology

121

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SummaryThe amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulin light chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis (ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associated with at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine for valine at position 30 is the most common mutation. Each variant has a different organ involvement, although clinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. This review combines clinical and laboratory findings of renal involvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteen nephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy. Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy is based on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, liver transplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is recommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in development may soon be available.

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Section: Clinical Presentationmentioning

confidence: 99%

Transthyretin Amyloidosis and the Kidney

Lobato

Rocha

2012

Clinical Journal of the American Society of Nephrology

121

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“…7 Some modifier genes such as amyloid P component, serum (APCS), complement C1QA and C1QC and plasma retinol-binding protein 4 (RBP4) have been unraveled so far but they only explain a small part of the AO variability in FAP ATTRV30M. 8,9 In a previous study, Soares et al 9 compared Portuguese patients in a classic casecontrol approach; these authors found that the variants studied in the APCS gene had a combined modifier effect when analyzing early-onset group versus controls, whereas the combination of one variant from APCS (rs6689429) and two variants from RBP4 (rs7091052 and rs28383574) seemed to be involved with late-onset group. 9 No comparisons were made between early-and late-onset cases.…”

Section: Introductionmentioning

confidence: 99%

Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M)

et al. 2015

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Familial amyloid polyneuropathy (FAP) ATTRV30M is a neurodegenerative disorder due to point mutations in the transthyretin gene, with V30M being the commonest. FAP ATTRV30M shows a wide variation in age at onset (AO) between clusters, families and generations. Portuguese patients also show remarkable AO differences between genders. Genes found to be associated with FAP ATTRV30M pathways may act as AO modifiers. Our aim was to further explore the role of APCS and RBP4 genes and to study for the first time the involvement of sex-linked genetic modifiers -AR and HSD17B1 genes -in AO variation in Portuguese families. We collected DNA from a sample of 318 patients, currently under follow-up. A total of 18 tagging SNPs from APCS, RBP4, AR and HSD17B1 and 5 additional SNPs from APCS and RBP4 previously studied were genotyped. To account for nonindependency of AO between members of the same family, we used generalized estimating equations (GEEs). We found that APCS and RBP4 were associated with late AO. In addition, rs11187545 of the RBP4 was associated with an early AO. For the AR, in the male group three SNPs were associated with an early AO, whereas in the female group four were associated with both an early and later AO. These results strengthened the role of APCS and RBP4 genes and revealed for the first time the contribution of AR genes as an AO modifier in both males and females. These findings may have important implications in genetic counseling and for new therapeutic strategies.

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“…Clustering has been proposed to play a role in the fibril formation of amyloidogenic proteins by stabilizing the TTR tetrameric structure, thus inhibiting TTR amyloidosis [17]. Identifying modified genes may offer hope and opportunities for pharmacological intervention in this uniformly lethal disease [18].…”

Section: Discussionmentioning

confidence: 99%