11p15.5

TAL,TAL-H,TALDOR,TALH

Hepatocellular carcinoma

Deletion of nucleotides 512-514 in TALDO1 resulted in the loss of serine 171 in the TAL protein and subsequent TAL deficiency (Verhoeven et al., 2001; Valayannopoulos et al., 2006). TAL deficiency results in the accumulation of sedoheptulose-7-phosphate and polyols. Further studies into TAL deficiency determined that the deletion of S171 resulted in a complete loss of enzymatic activity and rapid degradation in the proteasome (Grossman et al., 2004). Missense mutations at arginine 192, in which the arginine is mutated to either a histidine or cysteine, also results in loss of TAL activity and liver damage in patients (Verhoeven et al., 2005; Wamelink at al., 2008). In addition to liver damage, renal and cardiac complications are also present in these patients (Verhoeven et al., 2001; Valayannopoulos et al., 2006; Verhoeven et al., 2005; Wamelink et al., 2008).
In a mouse model of TAL deficiency, sperm dysmotility and subsequent male infertility are present (Perl et al., 2006). Furthermore, TAL deficiency results in the development of hepatosteatosis, cirrhosis, and hepatocellular carcinoma in both homozygous TAL knockouts and heterozygous mice relative to C57Bl/6 wild type mice (Hanczko et al., 2009). The pathogenic mechanism of liver damage in TAL deficiency is linked to depletion of NADPH, oxidative stress, and mitochondrial dysfunction (Perl et al., 2011). In TAL deficiency, it has been proposed that oxidative stress is exacerbated by increased aldose reductase activity which generates polyols and depletes NADPH (Perl et al., 2011). Low NADPH diminishes the cells ability to regulate cellular redox and polyols can induce proliferation through JNK/c-Jun (Perl et al., 2011). Thus, TAL deficiency and insufficiency predispose to oxidative stress which promotes liver damage, increased proliferation, and hepatocellular carcinoma.

Squamous cell carcinoma of the head and neck

3 SNPs in the TALDO1 gene have been associated with different squamous cell carcinoma of the head and neck risk. The conversion of cytosine to either guanine or thymine at 490bp upstream of the origin of replication (rs10794338) was protective against tumorigenesis (Basta et al., 2008). In contrast, the mutation of thymine to adenine at position 1874 (rs3901233) and adenine to cytosine at position 2187 (rs4963163) increase the risk of squamous cell cancer of the head and neck (Basta et al., 2008).