Cancer, genetic disorders

Congenital insensitivity to pain with anhidrosis; Anhidrosis; Autonomic neuropathy; Hereditary sensory and autonomic neuropathy Type V; Pyruvate kinase deficiency; Chagas disease; Relapsing fever; Dysautonomia

Congenital insensitivity to pain with anhidrosis (CIPA) is a genetic disease characterized by the inability to sense pain or temperature combined with reduced (or absent) sweating (anhidrosis). Symptoms of the disease generally appear at birth or soon after and may be complicated by prolonged healing from skin or skeletal injuries, which can manifest as chronic bone infections (osteomyelitis) or Charcot joints, a condition in which the bones and tissues of joints are degraded. This disease is inherited in an autosomal dominant manner. Analysis of CIPA patients revealed 11 novel mutations in the TRKA gene including 6 missense mutations, 2 frameshift mutations, 1 nonsense mutation, and 2 mutations producing abnormal splicing of the TRKA mRNA. The observed mutations were concentrated in either the extracellular NGF-binding domain of the TRKA protein or in an intracellular domain involved in downstream signal transduction. In animal studies, mice lacking the TRKA protein displayed a phenotype that closely resembled the symptoms of CIPA, including loss of response to painful stimuli. Additionally, the administration of MNAC13, a known antibody that neutralizes TRKA function, was shown to possess analgesic properties in mouse models of acute and chronic neuropathic pain. Autonomic neuropathy is a neurological disease characterized by defects in the autonomic nervous system (ANS), which carries information from the brain and spinal cord to the heart, bladder, intestine, sweat glands, pupils, and blood vessels. This disease has numerous symptoms, ranging from postural changes to digestive abnormalities. Loss-of-function mutations in TRKA have been observed in patients with this disease, reflecting the important role of NGF-TRKA signalling in the developmenal and survival of sympathetic neurons.
 

Granular cell tumours; Thyroid cancer; neuroblastomas; Adrenal neuroblastomas; Askin's tumours; Thyroid medullary carcinomas; Familial medullary thyroid carcinomas; Follicular thyroid carcinomas; NTRK1-related familial medullary thyroid carcinomas

TRKA appears to be an oncoprotein (OP). Overactive forms of the TRKA protein are known to have oncogenic properties and promote tumorigenesis. Chromosomal translocations involving the TRKA gene have been observed in thyroid papillary carcinoma tissue samples. Translocation t(1;3)(q21;q11) with the TFG gene creates the TRKT3(TRK-T3) mRNA transcript by the fusing of TFG to the 3'-end of TRKA. This translocation involves the replacement of the extracellular domain of the TRKA protein with the 221 N-terminal amino acids of the TPM3 protein. Additional observed chromosomal translocations include the fusion of the TPM3 gene to the 3'-end of TRKA mRNA, and an intra-chomosomal translocation that fuses the protein kinase catalytic domain to the 5'-end of the TPR gene to form the chimeric protein TRK-T1. These translocations are hypothesized to yield fusion proteins with constitutive tyrosine kinase activity, thus they represent gain-of-function mutations and the protein is considered as a oncoprotein.
 

The COSMIC website notes an up-regulated expression score for TRKA in diverse human cancers of 310, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than 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: 0.12 % in 25763 diverse cancer specimens. This rate is 1.7-fold higher than 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: 0.6 % in 854 skin cancers tested; 0.5 % in 1152 large intestine cancers tested; 0.33 % in 602 endometrium cancers tested; 0.28 % in 1944 lung cancers tested; 0.26 % in 575 stomach cancers tested; 0.14 % in 904 ovary cancers tested; 0.11 % in 1314 kidney cancers tested; 0.08 % in 1488 breast cancers tested.

None > 5 in 20,861 cancer specimens

Only 4 deletions, no insertions or complex mutations are noted on the COSMIC website.