NonHumanModel: Vervet Monkeys (Chlorocebus pygerythrus)

GeneAlteration: PCR amplification and direct sequencing indicated that all of the vervet monkeys observed and one of the malbrouck monkeys had the TTR Ile122 allele, as opposed to the the other primates (including humans) that harbor the Met122 allele. Other than this variant, the sequence was identical to three other species of monkeys that did not demonstrate amyloidosis phenotypes including 95-98%, 93-94%, and 76-81% amino acid homologies to humans.

ModelPhenotype: HP:0031327, HP:0003216, HP:0011675, HP:0012664 (Transthyretin cardiac amyloidosis, Generalized amyloid deposition, Arrhythmia, Reduced ejection fraction)

ModelFreeText: Haphazardly arranged rigid amyloid fibrils in the heart, Increased cardiothoracic ratio, Increased plasma ANP concentrations

HumanPhenotype: HP:0001627, HP:0011034 (Abnormal heart morphology, Amyloidosis)

HumanFreeText: N/A

ModelEvidence: Aged vervet monkeys were investigated for a naturally-occuring spontaneous systemic amyloidosis and accompanying phenotypes. PCR amplification and direct sequencing of these monkeys and others showed that the vervet monkeys alone harbored the Ile122 allele, as opposed to the more common Val122 allele in other primates and humans. Histopathological investigations showed cardiac amyloidosis and rigid amyloid fibers in the heart, identical to that observed in aged humans with the allele in question. These deposits were also found in other systems such as the gastrointestinal tract, adipose tissue, lung, tongue, and vascular walls, also mirroring the multiple locations they were found in humans. Immunoblotting confirmed that amyloid proteins extracted from the cardiac specimens reacted with anti-TTR antibody. Other cardiac symptoms were observed that mirror those in humans, such as arrythmia and reduced ehection fraction. Real-time PCR showed that these monkeys and humans shared the majority of TTR expression patterns. Recombinant monkey TTRs showed a greater tendency to dissociate to monomers under the influence of urea-mediated denaturation stress than recombinant TTR of the cynomolgus monkey, which had the Val122 allele. ThT-binding assay also showed a higher number of amyloid fibers in the recombinant than the cynomolgus.

ModelVariant: NM_000371.4(TTR):c.424G>A (p.Val142Ile)

ClinVar: 13426, https://www.ncbi.nlm.nih.gov/clinvar/variation/13426/