Cancer, eye, neurological, and immune disorders

Alexander disease (ALX); Hemimegalencephaly; Paronychia

Alexander Disease (ALX) is a rare disease which affects the brain. In ALX the white matter is destroyed and protein deposits (rosenthal fibers) replace the tissue, leading to speech abnormalities, difficulty swallowing, and lack of coordination in sufferers. Hemimegalencephaly is characterized by the enlargement of one side of the brain leading to an oversized and usually malfunctioning brain. Common symptoms in Hemimegalencephaly include impaired development, seizures, brain dysfunction, and spinal cord dysfunction. Paronychia is characterized by bacterial or fungal growth on the hand or foot, at the base of the nails.
 

Tuberous Sclerosis (TSC); Subependymal giant cell astrocytoma (SEGA); Lymphangioleiomyomatosis (LAM); Angiomyolipoma; Breast cancer; Tuberous sclerosis complex; Plasmablastic lymphomas (PBL); Ewing's family of tumours; Kidney angiomyolipoma

FRAP1 is a known oncoprotein (OP). Cancer-related mutations in human tumours point to a gain of function of the protein kinase. The active form of the protein kinase normally acts to promote tumour cell proliferation. FRAP1 has been linked with Tuberous Sclerosis, which is a rare disease that leads to a benign tumour growth in the brain and other organs. Tuberous Sclerosis often affects the skin, kidney, and brain. Subependymal Giant Cell Astrocytoma (SEGA) is a rare neuronal astrocytoma with a relation to the FSH signalling, and insulin receptor signalling pathways. Lymphangioleiomyomatosis (LAM) is a rare respiratory growth where LAM cells form cysts over time, and damage whichever tissue they reside in. LAM can also affect kidney, and smooth muscle. Angiomyolipoma is a benign tumour of the kidney, but can also affect the liver and lung. Tuberous Sclerosis Complex is characterized by the growth of benign tumours over the sufferer's body and can affect the skin, brain, and kidneys, among other tissues. Plasmablastic Lymphoma (PBL) is a rare cancer related to plasmacytoma and chronic lymphocytic leukemia. PBL can affect B cells, the spinal cord, and the liver. The rare cancer Ewing's Family of tumours is related to medullablastoma and cerebral primitive neuroectodermal tumour. Kidney Angiomyolipoma is related to the PI3K/Akt signalling pathway and the glioblastoma multiform pathway. In FRAP1 the S2159A and T2164A mutations together will lower autophosphorylation of the mTORC1-associated S-2481 residue. RPS6KB1 is phosphorylated more with the S2159D and T2164E mutations.
 

The COSMIC website notes an up-regulated expression score for FRAP1 in diverse human cancers of 395, which is 0.9-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 250 for this protein kinase in human cancers was 4.2-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. mTOR phosphotransferase activity can be increased with a T2173A mutation. Kinase phosphotransferase activity can be almost completely abrogated with a H2340A mutation. In FRAP1 the S2159A and T2164A mutations together will lower autophosphorylation of the mTORC1-associated S2481 residue. The substrate RPS6KB1 is phosphorylated more with the S2159D and T2164E mutations. The mTOR kinase phosphotransferase activity can be increased with a T2173A mutation. Its kinase phosphotransferase activity can be almost completely removed with a H2340A mutation.

Percent mutation rates per 100 amino acids length in human cancers: 0.08 % in 25904 diverse cancer specimens. This rate is very similar (+ 8% higher) to 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: 0.32 % in 1219 large intestine cancers tested; 0.26 % in 807 skin cancers tested; 0.24 % in 602 endometrium cancers tested; 0.21 % in 590 stomach cancers tested; 0.19 % in 1398 kidney cancers tested; 0.13 % in 1757 lung cancers tested; 0.11 % in 500 urinary tract cancers tested; 0.07 % in 605 oesophagus cancers tested; 0.07 % in 1498 breast cancers tested; 0.06 % in 984 upper aerodigestive tract cancers tested; 0.05 % in 905 ovary cancers tested.

Most frequent mutations with the number of reports indicated in brackets: S2215Y (10);S2215F (5); L2431P (7); R2505P (4); R2505Q (2); R2505L (1); I2500M (5); L2427Q (4); L2427R (3).

Nine deletions, and no insertions or complex mutations are noted on the COSMIC website.