Mutations in the transthyretin (TTR) gene are the most common cause of hereditary amyloidosis. Amyloidosis is caused by protein that is deposited as insoluble fibrils, mainly in the extracellular spaces of organs and tissues, as a result of changes in protein folding. Over 30 human proteins have been associated with different types of amyloidosis (Sipe et al., 2014; pubmed:25263598); intracellular protein inclusions are not typically included in this category (although they may be described as amyloid-like).
TTR encodes a transport protein prevalent in plasma and cerebrospinal fluid; this gene has also been implicated in familial carpal tunnel syndrome (OMIM:115430). There is a single orthologous gene in flies, CG30016, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple different UAS constructs of the human Hsap\TTR gene have been introduced into flies, including wild-type Hsap\TTR and genes carrying mutational lesions implicated in hereditary amyloidosis. Flies carrying mutant variants, but not wild-type TTR, exhibit changes in wing posture, locomotor defects, and shortened life span. These phenotypes are non-autonomous and are observed with an eye-specific driver as well as a pan-neuronal driver; the wing phenotypes are also observed with a fat-body-specific driver. Brains of aged adults show extensive vacuolation and staining by an amyloid-specific dye; expression in the eye results in observable neurodegeneration in both the eye and the brain.
Variant(s) implicated in human disease tested (as transgenic human gene, TTR): the L55P (L75P) and V30M (V50M) variants forms have been introduced into flies.
The fly CG30016 gene has not been extensively characterized; there is a single reported genetic interaction (see the CG30016 gene report). Since appropriate loss-of-function phenotypes have not been described, functional complementation by the human gene has not been tested.
[updated Jul. 2017 by FlyBase; FBrf0222196]
