Genetics Flashcards
I cell disease
Inability to phosphorylate mannose residues (phosphotransferase). Hydrolytic enzymes are not transported to the lysosome leading to macromolecules accumulating as inclusion bodies in the blood
Scurvy
Vitamin C deficiency. Decreased stability and tensile strength of collagen leads to: bleeding gums, hemorrhages and poor wound healing.
Lysl and proyl oxidase uses vitamin C as a cofactor to create hydroxyproline and hydroxylysine.
Ehler-Danlos Syndrome
Hereditary defect of enzymes needed for a current collagen synthesis and mutations in the genes encoding for alpha chains.
Type III: vascular form most severe due to lethal arterial rupture. Fragile skin and vascular walls.
Type V: Classic form Hypermobile joints and hyperextensibility of skin
Osteogenesis imperfecta
AD mutation in COL1A1 or COL1A2. Usually displacement of glycine in bone collagen which affects the formation and stability of the collagen triple-helix.
Type I mildest (OI Tarda): blue sclera
Type II most severe (OI congenita): death in uterine or soon after birth
Type III and IV are severe, but not as deadly: scoliosis and denial issues
Marfan
AD: Defect in fibrillin-1 (scaffolding), elastin is normal.
Long limbs, lens dislocation, arachnodactyly, aortic dilation, pectus excavatum
Immunodeficiency-centromeric instability-facial anomalies syndrome (ICF)
AR: Dnmt3b mutation
facial dysmorphism, mental retardation, recurrent/prolonged infections, and variable immune deficiency with a constant decrease of lgA.
Immunodeficiency associated w/ centromere instability of chromosomes 1, 9, and 16
Prader-Willi
Chromosome 15
Paternal deletion, maternal imprint. No SNRPN gene. Active UBE3A.
Maternal uniparental disomy
Mental/developmental delay, obese, underdeveloped genitalia
FISH, CGH
Angleman
Chromosome 15
Maternal deletion, paternal imprint
No copy of UBE3A, active SNRPN
Paternal uniparental disomy
Happy puppy syndrome, inappropriate laughter, severe intellectual disability, seizures
Rett Syndrome
X-linked dominant
Mutation in x-linked MeCP2 (methyl-cytosine binding protein 2)
Lethal in males. Affects mostly females. Normal development until 6-18 months. Then regression phase loss of speech/hand skills. Develop seizures, repetitive hand motions.
Beckwith-Wiedeman Syndrome (BWS)
Maternal rearrangement of 11p15, paternal uniparental disomy, abnormal methylation at 11p15
Macroglossia (large tongue), large birth weight, umbilical hernia, microcephaly, ear creases or pits
Increased risk with IVF
Incontinentia Pigmenti
X-linked dominant: IKBKG gene mutation. Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma
Males die in uterine
Variable expressivity due to x inactivation
Rashes and blisters in early life, hyperpigmentation later in life, possible retinal detachment, possible intellectual disabilities
Bloom Syndrome
Defect in BLM gene (DNA helicase) required for replication repair and recombination.
Chromosomal instability resulting in chromosomal breaks and sister chromatid exchange. Increased cancer risk
Butterfly facial rash upon sun exposure
Xeroderma Pigmentosum
AR and locus heteroginity
Nucleotide excision-repair. Mutations in 9 different NER genes can cause disorder.
Extreme sun sensitivity, skin cancer, neurological abnormalities
Ataxia Telangiectasia
AR: defects in ATM (11q22-23), a serine-threonine kinase
ATM detects DNA damage actives cell cycle arrest and DNA repair proteins
Double strand breaks
Affects cerebellum and immune system
Ocular telangiectasia common
Burkitt Lymphoma
Activation of MYC via t(8:14)
MYC (proto-oncogene) =TF translocated next to the promoter site of IgH. Always active.
Chronic Myeloid Leukemia (CML)
Philadelphia chromosome: t(9:22) creates BCR-ABL hybrid protein resulting in unregulated cytosolic tyrosine kinase
Treated with Imatinib mesylate (Gleevec)
Tyrosine kinase inhibitor
Oncogene
FISH
Li Fraumeni Syndrome
Inherited mutation in p53
Greatly increases risk for various cancers ata young age (breast, bone, brain, soft tissue carcinoma)
Tumor suppressor gene
Wilms Tumor
Renal cancer
Loss of function in WT1 gene chromosome 11 which encodes for TF controlling cell growth and differentiation
Tumor suppressor gene
Retinoblastoma
Rb
Tumor suppressor gene
BAX
Proapoptotic
P53
cell cycle arrests for DNA repair or apoptosis
BCL
inhibits BAX
Familial Adenomatous Polyposis (FAP)
Mutation in APC (Adenomatous Polyposis Coli) gene.
APC encodes for tumor suppressor whose role is to down-regulate growth promoting signals
Chromosome 5
APC = gatekeeper
Colorectal cancer: slow, multiple polyps
Hereditary Non-polyposis Colon Cancer (HNPCC)/ Lynch Syndrome
Mutations in mismatch repair proteins MSH2 and MLH1 resulting in microsatellite instability (Simple repetitive DNA tandem repeats)
Caretaker genes
Colorectal cancer: few polyps, rapid
Locus heterogeneity
Mismatch is a post-replicative repair mechanism
Down syndrome
Trisomy 21, 47 chromosomes
Single palmar crease,
Increased maternal age, meiotic nondisjunction during oogenesis meiosis I, Robertsonian translocation, mosaic
Edwards Syndrome
Trisomy 18
Nondisjunction during oogenesis
Clenched fist, overlapping fingers, rocker bottom feet, small lower jaw
47 chromosomes
Patu Syndrome
Trisomy 13
Nondisjunction during oogenesis
Polydactyl, cleft lip/palate, microphthalmia (small eyes)
Turner Syndrome
X0
Nondisjunction during spermatogenesis
Webbed neck, amenorrhea, gonad dysgenesis, can be mosaic if mitotic nondisjunction occurs during embryogenesis, NO BARR BODY
Sex chromosome aneuploidy
45 chromosomes
Klinefelter
Nondisjunction during meiosis I or II mom/ meiosis I dad
Gynecomastia, female hair distribution, infertility YES BARR BODY
Can be mosaic
Sex chromosome aneuploidy
47 chromosomes XXY
Cri-du-chat
5p loses genetic material from p15.3 to the terminal
Cat like cry, micrognathia (small jaw), hypertelorism
DiGeorge
Microdeletion 22
Absent thymus, cleft lip and palate, heart defect
Wolf-hirschhorn
Deletion on chromosome 4p
Roman helmet , facial anomalies, wide spread eyes, high arched eyebrows,
Robertsonian Translocations
Occurs between acrocentric chromosomes 13,14,15,21,22
Loss of short arm (p), fusion of long arm (q)
Kwashiorkor
Deficiency of dietary proteins
Decreased blood albumin, abdominal edema
Marasmus
Deficiency in carbs, lipids, proteins
Arrest growth, extreme tissue atrophy, emancipation, anemic, can be found in elderly
Lesch-Nyhan Syndrome
X-linked recessive
Deficienct HGPRT: inability to salvage purine bases, increased degradation, increased PRPP levels leading to de novo synthesis
Increased uric acid, severe mental impairment, SELF MUTILATION, gout
ADA Deficiency (SCIDS)
Deficiency in adenosine deaminase
DNA not synthesized in T and B cells because of an accumulation of dATP
Normally removes ammonia (deaminates) adenosine to inosine
Immunodeficiency, child morality due to overwhelming infections
Purine nucleoside phosphorylase deficiency (PNP)
Impairment of T-cell function
Decreased uric acid production and increased purine nucleosides and nucleotides
Removes ribose from inosine to form hypoxanthine
Thiopurine methyltransferase (TPMT) deficiency
Catalyzes a methylation reaction to inactivate 6-mercaptopurine
The drug (chemotherapy for leukemia) inhibit purine synthesis (can’t make RNA or DNA)
pts w/ this disorder need a reduced dose as they are at increased risk for myelosuppression (low RBC, WBC, and platelets)
Orotic Aciduria
Pyrimidine biosynthesis: deficient OPRT/OMP (UMP synthase).
Deficiency in Pyrimidines results in decreased RBC forming, DNA synthesis/cell division. (anemia). Improves with uridine. Normal ammonia levels
Urea cycle defect: Hyperammonemia Type II deficiency in ornithine transcarbamoylase. Increased amounts of carbamoyl phosphate that is formed in the mitochondria (urea cycle), diffuses into the cytosol and is used for pyrimidine biosynthesis, causing increased formation of orotic acid and orotic aciduria
BRCA 1 and BRCA 2
Involved in DNA repair or a apoptosis when DNA can’t be repaired (DSB)
Double strand breaks are repaired by non-homologous end joining (most common) and recombinational repair (less errors, uses homologous chromosomes)
Allelic heterogeneity
Tumor suppressor gene
ERBB2
Encodes for HER2 a tyrosine receptor
Breast cancer. Over expression of HER2 leads to constitutively active tyrosine kinase
Double minutes extrachromosomal elements
Treated with Herceptin (trastuzumab)
ERBB1
Encodes for the epidermal growth factor receptor (EGFR)
Point mutations cause constitutive activation of EGFR tyrosine kinase
Lung adenocarcinomas
RAS
Proto-oncogene
Activated by GTP
Cause phosphorylation cascade that activate cellular proliferation
Inhibited by intrinsic GTPase activity (GTP -> GDP)
Single point mutation at Gly12 or Gln61
