Biallelic inactivation of NKD1 was not observed, but the presence of wild type Nkd1 in tumor cell lines, as well as the ability of mutant Nkd1 to stabilize β-catenin, suggests that the NKD1 mutations might act dominantly (see below).
It was concluded that these mutations might act as major initiating mutations in this group.
To explain the lack of impact on iPPi observations, it was hypothesized that, in contrast to the ank/ ank recessive mouse mutant, the dominant human CPPD disease mutations might act as gain-of-function alleles that would moderately increase ePPi levels over time, leading to subtle abnormalities that have a minor and cumulative impact on articular cartilage homeostasis [ 15].
The N279K mutation might act on a proposed purine-rich exonic splice enhancer that reduces the relative expression of some 3R tau isoforms (D'Souza et al., 1999).
In 1999 Gatti et al. hypothesized that AT heterozygous carriers, which have one truncated version of the protein, behave differently from those with a missense mutation that might act as a dominant negative, which confers particularly high risk of breast cancer [ 219].
In addition, the lower penetrance of these mutations suggests that they might act in concert with other hereditary factors [ 6- 10].
In the case of amino acid mutations in TIN2 they might act by the same mechanism as a knock-down and leave telomere ends permanently unprotected in telomerase negative somatic tissues and thereby subject them to non-specific degradation.
To determine whether the stabilizing effects of the two single mutations T13D and F82D might act in a cooperative manner, we generated the IL-4 double variant T13D-F82D, weich wexpecteded to bind IL-4Rα with a KD in the sub-picomolar range.
Very recently, a high frequency of somatic mutations have been discovered in the promoter of telomerase reverse transcriptase (TERT) in cutaneous melanoma, resulting in increased transcriptional activity at the TERT promoter that might act as driver mutations (Horn et al, 2013; Huang et al, 2013).
However, this study did not distinguish between the effects of protein-truncating and missense mutations, although Gatti et al. [ 15] had hypothesised in 1999 that, compared with protein-truncating mutations, some missense variants in ATM might act as dominant negatives and confer a particularly high risk of breast cancer when heterozygous, although causing a milder form of AT when homozygous.
Gatti et al. [ 15] hypothesised in 1999 that, compared with protein-truncating mutations, some missense variants in ATM might act as dominant negatives and confer a particularly high risk of breast cancer when heterozygous, while causing a milder form of AT, when homozygous.
