TY - JOUR
T1 - Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met
AU - Dardiotis, Efthimios
AU - Koutsou, Pantelitsa
AU - Zamba-Papanicolaou, Eleni
AU - Vonta, Ilia
AU - Hadjivassiliou, Marilena
AU - Hadjigeorgiou, Georgios
AU - Cariolou, Marios
AU - Christodoulou, Kyproula
AU - Kyriakides, Theodoros
PY - 2009/9/15
Y1 - 2009/9/15
N2 - Background: Familial amyloidotic polyneuropathy (FAP) TTR Val30Met is a lethal autosomal dominant sensorimotor and autonomic neuropathy due to a substitution of methionine for valine at position 30 of the transthyretin (TTR) gene. Amyloid, composed of mutated TTR, is deposited in the peripheral nervous system, myocardium and kidneys. Considerable variability in the age of onset and penetrance of the disease occurs in different countries. Penetrance in Sweden, Cyprus and Portugal is 2%, 28% and 80% respectively. Environmental and genetic factors are believed to contribute to this variability. So far, no single modifier gene has been unequivocally associated with age of onset or penetrance. Methods: Candidate modifier genes were chosen from among those coding for chaperone proteins co-localized with TTR deposits in peripheral nerves. Seventy one TTRVal30Met carriers, 51 affected and 20 asymptomatic, belonging to 22 unrelated Greek-Cypriot families, and 59 normal controls were recruited for this study. Sequencing of the coding regions of TTR, serum amyloid P (APCS) and complement C1Q (A, B and C) genes was performed and APOE genotypes were determined. We searched for correlations between various polymorphisms of chaperone proteins and age of disease onset. Results: Four new and 4 previously described single nucleotide substitutions were identified. One polymorphic site in C1QA (rs172378) and one in C1QC (rs9434) as well as the ε2 allele correlated with age of onset (p < 0.05). Conclusions: Our study has identified polymorphisms which may influence the FAP-TTR Val30Met phenotype. Identifying modifier genes and their protein products may contribute to therapeutic advances.
AB - Background: Familial amyloidotic polyneuropathy (FAP) TTR Val30Met is a lethal autosomal dominant sensorimotor and autonomic neuropathy due to a substitution of methionine for valine at position 30 of the transthyretin (TTR) gene. Amyloid, composed of mutated TTR, is deposited in the peripheral nervous system, myocardium and kidneys. Considerable variability in the age of onset and penetrance of the disease occurs in different countries. Penetrance in Sweden, Cyprus and Portugal is 2%, 28% and 80% respectively. Environmental and genetic factors are believed to contribute to this variability. So far, no single modifier gene has been unequivocally associated with age of onset or penetrance. Methods: Candidate modifier genes were chosen from among those coding for chaperone proteins co-localized with TTR deposits in peripheral nerves. Seventy one TTRVal30Met carriers, 51 affected and 20 asymptomatic, belonging to 22 unrelated Greek-Cypriot families, and 59 normal controls were recruited for this study. Sequencing of the coding regions of TTR, serum amyloid P (APCS) and complement C1Q (A, B and C) genes was performed and APOE genotypes were determined. We searched for correlations between various polymorphisms of chaperone proteins and age of disease onset. Results: Four new and 4 previously described single nucleotide substitutions were identified. One polymorphic site in C1QA (rs172378) and one in C1QC (rs9434) as well as the ε2 allele correlated with age of onset (p < 0.05). Conclusions: Our study has identified polymorphisms which may influence the FAP-TTR Val30Met phenotype. Identifying modifier genes and their protein products may contribute to therapeutic advances.
KW - Familial amyloidotic neuropathy
KW - Modifier genes
KW - Transthyretin
KW - TTR Val30Met
UR - http://www.scopus.com/inward/record.url?scp=67849088532&partnerID=8YFLogxK
U2 - 10.1016/j.jns.2009.05.018
DO - 10.1016/j.jns.2009.05.018
M3 - Article
C2 - 19493541
AN - SCOPUS:67849088532
SN - 0022-510X
VL - 284
SP - 158
EP - 162
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
IS - 1-2
ER -