- cholesterol-uptake disrupted
- elevated LDL
- defect in gene for LDL receptor
- leads to atherosclerotic plaques
Familial hypercholesterolemia
- defect in peroxisomes (absent or reduced #)
- congenital
Zellweger spectrum disorders
Defect in transcription-coupled repair
mutations in ERCC6 and ERCC8
Growth retardation, skeletal abnormalities, sensitivity to sunlight
RNA polymerase is permanently stalled at sites of damage in important genes
Cockayne’s Syndrome
- lack 3’OH
- converted to dNTPs -> inhibit DNA replication
ex: - arabinosylctosine (ara-C, cytarabine) –> leukemia therapy
- acyclovir
- azidothymidine (AZT) –> HIV therapy
nucleoside analog inhibitors
skin is sensitive to light –> melanomas, carcinomas
–> thymidine dimers in DNA (cannot fix these due to defective NER complex)
xeroderma pigmentosum
mutation in MER complex
increased susceptibility to colorectal cancers
acquired mutation in good copy of gene -> MER system nonfunctional -> tumor development
hereditary nonpolyposis colorectal cancer
mutation in tumor suppressor genes (BRCA)
–> higher risk for other cancers
BRCA associated breast cancer
missense mutation in B-globulin of Hb (Glu -> Val)
(- charged -> hydrophobic branched AA)
change in Hb conformation –> aggregate/rigid rod-like structures -> poor O2 carrying capacity -> clog capillaries -> poor O2 supply to tissues
sickle cell anemia
X-linked, recessive -> mutation in muscle protein dystrophin (stabilizes the membrane w/ Ca2+ handling) –>
muscle wasting
Becker MD is a milder version
Duchenne Muscular Dystrophy
abnormal ptn: amyloid beta peptide (AB) -> AB plaques in the brain *extracellular
hyperphosphorylation of Tau (neurofibrillary tangles) *intracellular
symptoms:
- loss of memory, cognitive function, language
Familiar form: APP, Tau
Sporadic form: aging disease
Alzheimer’s disease
Parkinson’s disease
Abnormal ptn: a-synuclein (AS) forms insoluble fibrils -> Lewy bodies in dopa neurons in substantia nigra -> death of these neurons -> red. availability of dopamine
symptoms:
impairment of fine motor control
Familiar form: AS mutations
Sporadic form: aging
Huntington’s disease
Abnormal ptn: mutation in Huntington gene -> CAG repeats -> polyglutamine repeats -> intramolecular H-bonds -> misfold, aggregate -> death of basal ganglia cells
Symptoms: loss of movement and cognitive functions, psychiatric problems
*detected w/ VNTP (variable # tandem repeats)
Crutzfeldt-Jacob disease
Abnormal ptn: prion ptns, part of Transmissible spongiform encephalopathies (TSEs)
Symptoms: failing memory, behavior changes, lack coordination, visual disturbances
mental deterioration, blindness, weakness, coma
used in cancer treatments
ex: Etoposide, Fluoroquinolones
topoisomerase inhibitors
cross-linking agent -> prevents DNA replication/transcription
contains platinum ions
binds to plasma ptns -> concentrates in liver, kineys, intestine, and ovaries -> excreted in urine
* used for solid tumors
Cisplatin
