Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis

Abstract

A family with familial amyloidotic polyneuropathy (FAP) was previously found to have a substitution of asparagine for histidine at position 90 of transthyretin. Members with his90asn developed FAP. However, close examination of the transthyretin gene revealed that glu42gly is coinheri‐ted with his90asn in this family. Since glu42gly has already been seen in Japanese FAP patients, and his90asn has been found in Portuguese and German individuals without FAP, we conclude that his90asn is a nonpathogenic variant.

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

“…p.D119N has previously been reported to have a combined stability score comparable with wild-type variants and has been assumed to be benign based on a single report . It is unknown whether p.H110N is amyloidogenic, and to our knowledge, a stability score has not been reported . Another variant in the same codon, p.H110D (H90D), has recently been shown to be associated with familial amyloid polyneuropathy …”

“…31 It is disputed if p.H110N is amyloidogenic, and to our knowledge, a stability score has not been reported. 32,33 Transthyretin concentrations are expressed as median and interquartile range and risk of heart failure as hazard ratios from Cox regression models and 95% CIs. Analyses were adjusted for age (underlying timeline) and stratified by study cohort.…”

“…31 It is unknown whether p.H110N is amyloidogenic, and to our knowledge, a stability score has not been reported. 32,33 Another variant in the same codon, p.H110D (H90D), has recently been shown to be associated with familial amyloid polyneuropathy. 34 Using heterozygotes for p.T139M, the most stable variant, as the reference group, we observed a stepwise reduction in transthyretin concentration, from a median (IQR) of 32.1 (25.6-37.2) mg/dL in p.T139M heterozygotes, to 26.8 (22.1-31.6) mg/dL in wild-type variants (−16.5% compared with p.T139M variant), 26.3 (21.9-30.9) mg/dL in the p.G26S variant (−18.1% compared with p.T139M variant), 22.7 (21.6-25.7) mg/dL in the p.D119N variant (−29.3% compared with p.T139M variant), 21.3 (14.6-24.9) mg/dL in the p.H110N variant (−33.6% compared with p.T139M variant), and 19.8 mg/dL in the p.V142I variant (−38.3% compared with p.T139M variant) (P for trend < .001) (eFigure 7 in the Supplement).…”

Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation

“…Some mutations, such as G6S46 or H90N47 have a negligible impact on TTR stability and are considered non-pathogenic, whereas others like R104H48 or T119M30 have been shown to act as trans-suppressors. Trans-suppressor mutations render TTR more stable against dissociation and aggregation, reducing the symptoms of the disease in heterozygotes carrying additional aggressive mutations in the other allele.…”

Transthyretin asn90 variant: Amyloidogenic or non-amyloidogenic role

“…The His 90Asn mutation in exon 3 of TTR gene was described [13,19] both in families with classical phenotype of FAP and in subjects asymptomatic for FAP, suggesting that two different isoelectric point patterns can distinguish amyloidogenic and non-amyloidogenic TTR mutations [20]. This finding raises some uncertainties on mutation pathogenetic effects.…”