Musculoskeletal disorders

Dystonia 3, torsion, X-linked; Dystonia; X-linked dystonia-Parkinsonism; Spinocerebellar ataxia Type 17

Loss-of-function mutations in the TAF1 gene that decrease the kinase catalytic activity of the protein have been observed in dystonia patients. A 2,627 bp SVA retrotransposon insertion into intron 32 of the TAF1 gene has been hypothesized as the causal mutation responsible for the high frequency of X-linked dystonia-Parkinsonism in a Filippino population on Panay Island. Dystonia is a group of muscle diseases that are characterized by sustained muscle contractions which cause twisting, repetitive movements, or abnormal posture. The movements are involuntary, may be painful, and can affect a single muscle group, a group of muscles (e.g. arm, leg, neck), or all the muscles of the body. Roughly half of the occurence of dystonia is idiopathic and appears to be inherited, referred to as a primary dystonia. X-linked dystonia-Parkinsonism has a well defined pathology consisting of degeneration of the striatum (caudate nucleus and putamen), resembling the pathology of Huntington disease.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Brain glioblastomas (%CFC= -66, p<0.064); Brain oligodendrogliomas (%CFC= -90, p<0.019); Cervical cancer stage 2A (%CFC= +98, p<0.036); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +460, p<0.001); and Ovary adenocarcinomas (%CFC= +51, p<0.019). The COSMIC website notes an up-regulated expression score for TAF1 in diverse human cancers of 591, which is 1.3-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 192 for this protein kinase in human cancers was 3.2-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 25009 diverse cancer specimens. This rate is the same as the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.37 % in 603 endometrium cancers tested; 0.26 % in 1372 large intestine cancers tested; 0.19 % in 589 stomach cancers tested; 0.14 % in 864 skin cancers tested; 0.14 % in 1637 lung cancers tested; 0.12 % in 273 cervix cancers tested; 0.11 % in 548 urinary tract cancers tested; 0.1 % in 833 ovary cancers tested; 0.09 % in 1512 liver cancers tested; 0.08 % in 1409 breast cancers tested; 0.07 % in 710 oesophagus cancers tested; 0.05 % in 1276 kidney cancers tested; 0.04 % in 238 bone cancers tested; 0.04 % in 2094 haematopoietic and lymphoid cancers tested; 0.04 % in 2082 central nervous system cancers tested; 0.04 % in 1459 pancreas cancers tested; 0.04 % in 127 biliary tract cancers tested; 0.03 % in 881 prostate cancers tested; 0.02 % in 942 upper aerodigestive tract cancers tested; 0.02 % in 441 autonomic ganglia cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R843W (5); R1442Q (4); R1442W (2); E651G (3).

Only 6 deletions, 2 insertions, and 3 complex mutations are noted on the COSMIC website.