Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is a familial cancer syndrome caused by mutations in the APC gene. In FAP, adenomatous polyps are present in the colon. The polyps progress into colon cancer unless removed. The APC gene is a tumor suppressor. Its protein product is involved in many cellular processes. Inactivation of the APC gene leads to the buildup of a protein called β-catenin. This protein activates two transcription factors: T-cell factor (TCF) and lymphoid enhancer factor (LEF). These factors cause the upregulation of many genes involved in cell proliferation, differentiation, migration and apoptosis (programmed cell death), causing the growth of benign tumors. Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in the genes TSC1 and TSC2. TSC1 produces the protein hamartin. TSC2 produces the protein tuberin. This disorder presents with many benign hamartomatous tumors including angiofibromas, renal angiomyolipomas, and pulmonary lymphangiomyomatosis. Tuberin and hamartin inhibit the mTOR protein in normal cellular physiology. Inactivation of the TSC tumor suppressors causes an increase in mTOR activity. This leads to the activation of genes and the production of proteins that increase cell growth. Von Hippel–Lindau disease
Von Hippel–Lindau disease is a dominantly-inherited cancer syndrome that significantly increases the risk of various tumors. This includes benign hemangioblastomas and malignant pheochromocytomas, renal cell carcinomas, pancreatic endocrine tumors, and endolymphatic sac tumors. It is caused by genetic mutations in the Von Hippel–Lindau tumor suppressor gene. The VHL protein (pVHL) is involved in cellular signaling in oxygen starved (hypoxic) cells.
Patients experience optic atrophy due to progressive cranial nerve compression, which may lead to nystagmus or even blindness in severe cases.Other neurological abnormalities include intellectual disability, speech and psychological deterioration. Convulsions and status epilepticus are also present in patients, however the mechanisms for the development of these features are unknown. Patients also experience cranial nerve damage resulting from progressive cranial pressure. Pathogenesis
DSS is classified as an autosomal recessive disease(OMIM 224300), but it is also identified as an X-linked recessive inheritance in certain families. The total number of genes that are responsible for causing the disease and the correlation between genotype and phenotype remains unclear. Multiple gene mutations were identified in different patients via whole genome sequencing, therefore it is presumed that DSS is genetically heterogeneous. TCIRG1 mutation
The TCIRG1 gene is present in chromosome locus 11q13, which encodes for the a3 subunit of vacuolar H+ ATPase (V-ATPase) that is unique to osteoclasts. The a3 subunit is responsible in anchoring the vacuolar proton pump to the ruffled membrane of osteoclasts. The V-ATPase is important in mediating the transport of hydrogen ions into the resorption lacunae, which is a pit on the bone surface enclosed by the osteoclast for bone resorption. The accumulation of ions in the lacuna facilitates the decomposition of hydroxyapatite crystals by creating an acidic environment, resulting in bone resorption. Mutation of the gene results in osteoclast-rich osteopetrosis due to poor translation and altered structure of proton pump structure, which is normally involved in large amounts of osteoclast activity leading to absorption of bone tissue.