Genetics Flashcards
BMPR2
Primary arterial hypertension
Abnormal endothelial and vascular smooth muscle growth and proliferation
Young healthy appearing women
Poor prognosis
Alpha 1-antitrypsin deficiency
Chromosome 14
Normally inhibits elastase
Deficiency results in early onset panacinar emphysema in LOWER lung
Some patients also present with liver cirrhosis due to alpha1 build up in liver that occurs with phenotypes that experience pathologic polymerization of AAT in ER of hepatocytes
Kartageners syndrome
Mutation of dynein protein - ciliary dyskinesia
Chronic sinusitis, Bronchiectasis, male infertility, situs inversus
Classic case: child with recurrent sinus/ear infections, chronic cough, Bronchiectasis on CT, obstruction on PFTs, situs inversus
MYD88 Mutation
severe necrotizing lobar pneumonia due to strep pneumo
Phe508
aka delta-F-508 gene mutation
AR - Cystic fibrosis
Results in non-frameshift deletion
Chromosome 7 - CFTR gene
Factor 5 Leiden Mutation
Most common inherited hypercoaguability in caucasians
production of mutant factor 5 (Arg506Gln point mutation near cleavage site) AD. resistant to degredation by activated protein C (APC). Result is accelerated prothrombin activation
Complications: DVT, cerebral vein thromboses, recurrent pregnancy loss
protein C or S deficiency
Nonsense mutation AD - Decreased ability to inactive factor V and VIII
Complications: VTE, warfarin-induced skin necrosis, neonatal purpura fulminans
Antithrombin III deficiency
AD. Two types
1. reduced synthesis
2. Functionally defective
Complications: VTE - VERY HIGH RISK
Prothrombin mutation
AD. mutation in 3’ UTR - results in increased prothrombin production and thus high prothrombin plasma levels and VTE
EGFR
Proto-oncogene - receptor tyrosine point mutation that causes spontaneous dimerization in abscence of a ligand
mutation seen commonly in lung cancer (adenocarcinoma)
Target of personalized treatment
(90-100% of epithelial head and neck tumors also have EGFR)
ERBB2 (HER2/NEU)
Breast cancer tyrosine kinase receptor point mutation
ALK
non-receptor tyrosine kinase
Seen in NSCLC as well (young non-smokers - adenocarincoma)
Results in EMLA4-ALK fusion protein that allows auto dimerization. Diagnose with FISH
Ras
most commonly mutated proto-oncogene in human tumors
Point mutation of downstream signaling molecule in cell growth. Prevents Ras from kicking off GTP and is thus constituitively active
Seen in most pancreatic cancers
Also in 1/2 of colon, endometrial, and thyroid cancer. 1/3 of lung cancer
B-Raf
directly downstream of Ras. Mutated in melanoma, NSCLC, colorectal cancer
Retinoblastoma Protein (Rb)
Tumor suppressor that modulates G1 restriction point.
Normally binds to EF2 and prevents transcription unless phosphorylated by Cdk2
Mutations range from cytogenetic deletions, point mutations, and promoter hypermethylation and result in loss of function
NOTE: gain of function mutations in cyclin or Cdk, or decreased CDKI activity have similar effect
Retinoblastoma
13q
most common ocular malignancy in childhood
1:3 have germline mutation in Rb protein
Presentation: Leukocoria, strabismus, uveitis, glaucoma
“Leukocoria and loss of red reflex
Adenomatous polyposis coli (APC) gene
Normally inhibits beta catenin (transcription factor) and thus inhibits transcription. Release B-catenin in response to WNT signaling.
Mutation results in beta catenin accumulation and thus growth promotion
Seen in 70% of sporadic colon cancers
*WNT signaling: controls cell fate, adhesion, and polarity
Familial Adenomatous polyposis
5q
AD APC gene mutation leading to inappropriate WNT signaling
100s-1000s of polyps develop in colon by early 20s. Develop cancer by age 35-50
p53
Tumor suppressor: guardian - monitors cellular stress
most frequently mutated gene in human caner
Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
o Anoxia, DNA damage, oncogene signaling →ATM/ATR kinases phosphorylates p53→active
o Cell cycle arrest at G1/S checkpoint→either repair or apoptosis
MDM2 targets p53 for degredation
Li Fraumeni syndrome
AD germline mutation
One p53 allele mutated –> cancer syndrome
25x increase in cancer risk by age 50
Lynch syndrome
MSH2, MLH1 mutation
Von Hippel-Lindau Syndrome
o AD mutation in VHL protein, which normally regulates ubiquitination
o Result: defective or absent VHL → accumulation of undegraded products
o Clinical presentation: Retinal and CNS hemangioblastomas
o Pheochromocytomas
o Cysts in kidneys and pancreas
Down syndrome
Early onset alzheimers (additional APP + SOD1)
Chromosome 21 – trisomy is primary cause. However, robertsonian translocation “rob (14,21) (q14, q21)” is cause in small number of cases. Results in triploid
Parent pass on normal 21 and the 21,14 combo. Then other parent passes normal 21 and patient is effectively triploid
Presentation: epicanthal folds, dysplastic ears, horizontal palmar crease, redundant neck skin, short trunk
Comorbidities: duodenal atresia, trachesophageal fistula, leukemia
Turner syndrome
45 XO - Short stature, webbed neck
lymphedema in hands and feet, skeletal abnormalities, congenital heart defects, infertility
Patau Syndrome
47, +13 (think - Puberty, 13)
intellectual disability, microcephaly, microphtalmia, polydactyly, cleft lip and palate
renal defects and cardiac abnormalities
Die before age 1
Fragile X syndrome
X-linked DOMINANT
CGG trinucleotide repeat in FMR1 gene leading to hypermethylation and decreased expression
Macroorchidism in males (enlgared testes after puberty), large ears, prominent jaw and forehead
Klinefelter syndrome
47, XXY
male with impaired sexual development, small testes unable to produce sufficient testosterone–>delay/incomplete puberty, gynecomastia, micropenis, undistended testes, infertility, tall
Neurofibromatosis 2
bilateral acoustic neuromas, juvenile cataracts, meningiomas and ependymomas – effects 2 eyes, 2 ears, 2 parts of brain, chromosome 22
Von hippel lindau
3p (3 letters)
VHL regulates HIF1 - mutated protein cant bind
angiomas, hemangioblastomas of CNS retina and spine, phepchromocytoma, bilateral renal cell carcinoma
Neurofibromatosis 1
17, AD
Neurofibromin (negative regualtor of RAS) is mutated
Von Recklinghausen (17 yo are reckless)
cafe au lait spots (freckling of skin), neurofibromas, Lisch nodules, increased risk for astrocytomas
