Human Disease Model Report: amyloidosis, hereditary, transthyretin-related
Human Disease Model Report: amyloidosis, hereditary, transthyretin-related
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]
[AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED](https://omim.org/entry/105210)
[TRANSTHYRETIN; TTR](https://omim.org/entry/176300)
Patients with transthyretin amyloidosis typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. In later stages of the disease severe diarrhea with malabsorption, cachexia, incapacitating neuropathy, severe cardiac disturbances, and marked orthostatic hypotension dominate the clinical picture. Death usually occurs 5 to 15 years after onset of symptoms [from OMIM:105210; 2016.07.29]
Mutations in the transthyretin (TTR) gene are the most common cause of hereditary amyloidoses. Familial amyloidoses are a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the aggregation of misfolded proteins and deposit of unsoluble protein fibrils in the extracellular matrix (summary by Hund et al., 2001; pubmed:11261421). [from OMIM:105210; 2016.07.29]
More than 100 different mutations in the transthyretin gene have been reported to be implicated in familial amyloidosis; the most common is V30M. Different TTR mutations are associated with amyloidosis that affects different organ systems. [from NORD, Amyloidosis; 2016.07.27] The most common organs affected are peripheral nerves and/or the heart. [from Gene Cards, TTR; 2016.07.27]
The transthyretin molecule consists of a tetramer of identical 127-amino acid subunits. Transthyretin is a plasma transport protein for thyroxine (T4) and for retinol (vitamin A), through the association with retinol-binding protein (RBP4) (summary by Saraiva, 2001; pubmed:11385707). [from OMIM:176300; 2016.07.29]
One to one: 1 human to 1 Drosophila.
Ortholog of human TTR (1 Drosophila to 1 human). Dmel\CG30016 shares 26% identity and 44% similarity with human TTR.
