Genetics Flashcards
Which gene mutation is a/w Breast Ca & Pancreatic Ca ??
BRCA2
Which cancer is a/w TP-53 mutation ??
Li- Fraumeni synd.
- A D inheritance
- It normally functions as a tumour suppressor gene
- a/w increased risk of Bone & Soft tissue cancer ; even breast cancer
Which cancers are a/w BRCA2 mutation ??
Breast & Ovary
Pancreatic
Prostate
Stomach
Bile duct & GB
Melanoma
Gene mutation a/w Burkitt’s Lymphoma ??
c-myc gene
t [8, 14]
What is Peutz- Jeghers synd. ??
- A D
- Perioral & mucosal melanocytic pigmentation
- Hamartomatous polyp
a/w Colorectal Ca, Gastric, Small bowel & Pancreatic Ca - increased risk of Breast Ca»Ovarian»Cervical
What is Gardner synd. ??
Famial Adenomatous Polyposis
- a/w Early onset Colon Ca
- Can also cause Osteomas, Epidermoid cyst
What is Lynch synd. ??
HNPCC
- a/w Early presentation, mean age of dx. 44- 61 yrs
- a/w GASTRIC & ENDOMETRIAL Ca
Fabry’s disease inheritance pattern ??
X- linked Recessive disorder
BRAF mutation ??
encodes B-raf protein
- MAP-kinase signalling pathway => regulates Cell division & differentiation
- Malignant melanoma
How to differentiate b/w Marfan’s & Homocystinuria ??
- Fibrillin 1 deficiency + NOT a/w low IQ + Upward lens dislocation
- Cystathione Beta-synthase deficiency + Low IQ + Downward lens dislocation + A R + VTE & MI
What is Pseudoxanthoma elasticum ??
ATP-binding Cassette protein, family C no. 6 mutation
- Puckered chicken skin
- Angiod retinal streaks
- Accelerated CVS disease
Below what age does the the Abd. USS screening of ADPKD is (-)ve
< 20 yrs
Gene involved in A R Polycystic Kidney Disease ??
PKHD1
What is DNA Methylation ??
Suppresses gene transcription
- occurs at 5th position of Cytosine, has the specific effect of reducing gene expression
How are mitochondrial disorders inheritted ??
Maternal lineage
What is the best way to edit the genome ??
CRISPR/Cas9 technology
What percentage of human genome is made of Non-coding sequence ??
90% of genome is comprised of Non-coding DNA
What are the cell cycle phases ??
G 0: Resting phase (eb.- hepatocytes, Neurons)
G 1:
- Increase in size
- Determines the LENGTH of Cell Cycle
- Under p53 influence
S phase: DNA, RNA & Histone synthesis; Centromere duplication
G 2 : Cell continue to increase its size
M : Mitosis- Cell division
Name the following about the Cell Cycle
- Under p 53 influence ??
- Determines the length of Cell C ??
- Centromere Duplication ??
- Shortest phase of Cell C ??
- G 1
- G 1
- S phase
- M phase
Name the Regulatory proteins of the following
- G 1 phase ??
- Transition from G 1 to S phase ??
- S phase ??
- G 2 phase ??
- Cyclin D/ CDK4, Cyclin D/ CDK6
- Cyclin E/ CDK2
- Cyclin A/ CDK2
- Cyclin A/ CDK1
What are the phases of Mitosis ??
Prophase: Chromatin condenses in the nucleus
Prometaphase: Nuclear memb. breaks down + Microtubules attach to Chromosomes
Metaphase: Chr. aligned at MIDDLE of cell
Anaphase: Paired Chr. SEPERATE at Kinetochores & move to the opposite end
Telophase: Chromatids arrive at the poles of the cells
Cytokinesis: Actin-Myosin complex in the centre of the cell contracts => Cell being pinched into 2 daughter cells
What are Microtubules ??
Components of Cytoskeleton of Cytoplasm
- Guide movt. during intracellular transport
- Helps to BIND internal organelles
Cylindrical str. composed of Alpha + Beta tubulin subunits => polymerize to form PROTOFILAMENTS
- They are POLARIZED
How does molecular transport occur with the help of Microtubules ??
Attachment proteins called DYNEIN & KINESIN move up & down the Micro-tubules facilitating the movt. of organelles around the cell
- Dynein=> moves in Retrograde fashion- DOWN the microtubules towards the centre of cell [+ve => -ve]
- Kinesin=> moves in Anterograde fashion- UP the microtubule away from the centre, [-ve ==> +ve]
Name the Cell Surface Proteins a/w the following cells
- Haematopoietic Stem Cells ??
- Helper T cells ??
- Cytotoxic T cells ??
- Regulatory T cells ??
- B cells ??
- Macrophages ??
- NK cells ??
- CD 34
- CD4, TCR, CD3, CD28
- CD8, TCR, CD3, CD28
- CD4, CD25, TCR, CD3, CD28
- CD19, CD20, CD40, MHC-II, B7
- CD14, CD40, MHC-II, B7
- CD16, CD56
Name the Types of Memb. Receptors ??
4 main types
LIGAND-GATED ion channel receptors
- Fast responses
- eg.- Nicotinic ACh, GABA-A, GABA-C, Glutamate receptors
TYROSINE KINASE Receptors
- Receptor Tyrosine Kinase
- Non-receptor Tyrosine Kinase
GUANYLATE Cyclase Receptors
- Contains Intrinsic enzyme activity
- eg.- BNP, ANP
G-PROTEIN Coupled Receptor
Name the types of T K receptors ??
Receptor Tyrosine Kinase
- Insulin, Insulin like Growth Factor (IGF), Epidermal G F
Non-Receptor Tyrosine Kinase
- PIGG(L)ET
- Prolactin, Immunomodulators (IL2, IL6, IFN), GH, G-CSF, EPO, Thrombopoietin
What are the types of G-Protein Coupled Receptors ??
- Mediate SLOW transmission
- Activated by a various extracellular signals: Peptide hormones, Biogenic amines (eg- Adrenaline), Lipophilic Hormones
- 7-helix memb.-spanning domains
- 3 main subunits: Alpha, Beta, Gamma
- G-proteins according to ALPHA subunits: Gs, Gi, Gq
How is the Alpha subunit activated in G-Protein coupled receptors ??
[Alpha is linked to GDP] => Ligand binding => Conformational changes to receptor => GDP is Phosphorylated to GTP => Alpha activated
How does Gs, Gi & Gq work ??
Gs: (+) Adenylate cyclase => increases cAMP => activates Protein kinase A
Gi: (-) Adenylate cyclase => decreases cAMP => (-) PK-A
Gq: Activates Phospholipase C => splits PIP-2 to IP3 + DAG => Activates PK-C
Give eg. of Gs, Gi & Gq receptors
- Gs : Beta-1 (NE, E, Dobutamine), Beta-2 (E, Salbuterol), D1 (DA), H2 (Histamine), V2 (vasopressin), Receptors for ACTH, LH, FSH, Glucagon, PTH, Calcitonin, PGs
- Gi : M2 (ACh), Alpha-2 (NE, E), D2 (DA), GABA-B receptor
- Gs : Alpha-1 (NE, E), H1, V1, M1 & M3 (ACh)
Which is the MC 2nd messenger pathway ??
cAMP pathway
Name the site of Erythropoiesis in
- Adults
- Foetus
- Red B M: Flat Bones (including Vertebrae, Ribs, Sternum) & Proximal ends of Long bones
- Mainly LIVER
What are the 2 types of Precursor cells derived from Haematopoietic Stem Cell ??
LYMPHOID & MYELOID
- RBCs originate from Myeloid; regulated by EPO based on DECREASED O2 levels in blood
- RBCs synthesis takes 1 wk & lives for 120 days
What does the following Molecular Biology techniques detect ??
- Southern Blotting
- Northern Blotting
- Western Blotting
SNOW DROP
South-NOrth-West = Dna-Rna-Protein
- Detects DNA
- Detects RNA
- Detects Protein (uses electrophoresis to separate native proteins by 3D structure (eg.- HIV test confirmation)
What is ELISA ??
Type of Biochemical Assay used to detect Antigens & Antibodies
Colour changing enzyme is attached to
- Antibody if looking for antigens
- Antigen if looking for antibody
Sample therefore changes colour if the antigen or antibody is detected
Name the tests used for
- Initial detection of HIV ??
- Confirmation of HIV ??
- ELISA
- Western Blotting
Uses of PCR technique ??
- Prenatal Dx.
- Detection of mutated Oncogenes
- Dx. of Infection
- FORENSICS
Steps involved in PCR technique ??
Sample DNA + 2 DNA Oligonucleotide Primers
- A Themostable DNA Polymerase (Taq) is added
Then the following steps are repeated
- DENATURATION (94- 96 C)
- ANNEALING (68 C)
- ELONGATION (72 C)
What is a General rule regarding A D & A R disorders with exceptions ??
A R = are often METABOLIC
A D = are often STRUCTURAL
Exceptions:
- Metabolic conditions eg.- Hunter’s, G6PD are X-linked R & Hyperlipidaemia type 2, HypoK+ Periodic Paralysis are A D
- Structural conditions eg.- Ataxia Telangiectasia & Friedreich’s Ataxia are A R
Name a few Mitochondrial diseases ??
- Leber’s Optic Atrophy
- MELAS syndrome: Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes
- MERRF synd.: Myoclonus Epilepsy with Ragged Red Fibres
- Kearns-Sayre Synd.: <20yrs, External Ophthalmoplegia, Retinitis pigmentosa, Ptosis
Hallmark features of Mitochondrial diseases ??
Mitochondrial DNA normally encodes protein components of the Respiratory chain & some special types of RNA
- Inheritance: MATERNAL line only
- NO children of an affected male will inherit
- ALL children of an affected female will inherit
- Generally encodes Rare CNS disease
Poor Genotype : Phenotype correlation
HP: Muscle biopsy shows ‘Red ragged fibres’ due to increased mitochondria
What is Penetrance ??
“How likely” it is that a condition will develop
- Eg. of conditions with Incomplete penetrance: Retinoblastoma, Huntington’s disease
- Eg. of conditions with Complete penetrance: Achondroplasia
What is Expressivity ??
Describe the “Severity” of phenotype or the extent to which a genotype shows its phenotypic expression
- Eg. NF has high level of expressivity
What is McCune-Albright Syndrome ??
NOT an Inherited disorder
Random, Somatic Mutation in the GNAS gene
- Precocious puberty + Cafe-au-lait spots + Polyostotic fibrous dysplasia
- Short stature
What is William’s Synd. ??
Inherited Neuro-developmental disorder; caused by MICRODELETION on Chr. 7
- Elfin-like facies + [very Friendly & Social] + Learning difficulty
- Short stature
- Transient Neonatal HyperCa2+
- Supravalvular AS
How is William Synd. Diagnosed ??
FISH studies (Fluorescence in-situ Hybridization)
What is Genetic Imprinting ??
Inheritance pattern where the Phenotype depends on whether the deletion occurs on a gene inherited from the mother or father
- Prader-Willi Synd.: If gene
—–Micro-deleted from father (15q11-13) 70% cases (OR)
—–Maternal Uniparental disomy of Chr.-15q
- Angelman synd.: If gene deleted from Mother on Chr. 15
Features of Prader-Willi Synd. ??
- Hypotonia during Infancy
- Dysmorphic features
- Short stature
- Hypogonadism & Infertility
- Learning difficulty
- Childhood Obesity
- Behaviour problems in Adolescence
What is Achondroplasia ??
A D disorder (30% cases) a/w Short stature
- Mutation in Fibroblast Growth Factor receptor- 3 [FGFR-3] gene
- Results in Abnormal Cartilage
Maj. (70% cases) occurs due to SPORADIC mutation
- Main risk factor: Advancing Parental age at conception time
Features of Achondroplasia ??
- Rhizomelia (short limbs) + Short fingers (Brachydactyly)
- Large head with Frontal bossing
- Narrow Foramen Magnum
- Midface Hypoplasia with Flat Nasal bridge
- Trident hands
- Lumbar lordosis
Mention the Risk of Down’s syndrome with Maternal age
20 yrs = 1 in 1500
30 yrs = 1 in 800
35 yrs = 1 in 270
40 yrs = 1 in 100
45 yrs = 1 in 50 or greater
How does Trisomy 21 occur in Down’s syndrome ??
Nondisjunction (94% cases): 1 in 100 if mother < 35yrs
Robertsonian translocation (onto 14)
- 5% cases
- 10-15% if mum & 2.5% if dad is a translocation carrier respectively
Mosaicism (1% cases)
- Presence of 2 genetically different population of cells in the body.
MC cardiac defect in Trisomy 21 ??
Down’s Syndrome
- Endocardial Cushion defect (40%) aka AV Septal Canal defect
- VSD (30%)
- Secundum ASD (10%)
- ToF (5%)
- Isolated PDA (5%)
What is Turner’s Synd. ??
Chromosomal disorder; affects 1 in 2500 FEMALES
- One X Chr. or Deletion of SHORT arm of 1 of the X Chr.
- 45, X0 or 45, X
Cardiac defect & Renal defect seen in Turner’s ??
- Bicuspid AV (15% cases)
- Coarctation of Aorta (5- 10%)
Horseshoe kidney
[Cystic hygroma is often Dx. Prenatally]
What is Noonan’s Synd. ??
A D condition a/w Normal Karyotype
“Male Turner’s”
Chr. 12 defect (‘Noon’an)
Name the Cardiac & Coagulation problems seen with Noonan’s Synd. ??
Pulmonary Valve Stenosis
Factor XI defect
What is Fabry’s disease ??
X-linked Recessive
Alpha-Galactosidase A deficiency
- Burning pain/ Paraesthesia in childhood
- Angiokeratomas
- Lens opacities
- Proteinuria
- Early CVS disease
- Decreased sweating
Rx.- Synthetic Alpha-GAL A
What is Fragile X syndrome ??
Trinucleotide Repeat Disorder (CGG)
Features in MALES
- Learning difficulty
- Large low set ears, Long thin face, High arched palate, Hypotonia
- Macro-orchidism
- Mitral Valve Prolapse
Features in FEMALES
- They have 1 Fragile X & 1 Normal X
- Normal to Mild symptoms
How can Fragile X syndrome be Diagnosed ??
Antenatally
- Chorionic Villi Sampling
- Amniocentesis
CGG analysis is done by using Restriction Endonuclease digestion & Southern Blotting
What is the pathophysiology of Alkaptonuria ??
A R condition aka OCHRONOSIS
- Disorder of Phenylalanine & Tyrosine metabolism
- Lack of enzyme Homogentisic Dioxygenase (HGD) ==> build up of toxic Homogentisic acid => Kidney filters this => BLACK Urine & Eventually accumulate in Cartilage & other tissues
Features of Alkaptonuria ??
Benign & Asymptomatic condition but ca cause the following C/F
- Pigmented Sclera
- Urine turns black when left exposed to air
- Intervertebral Disc Calcification => Backpain
- Renal Stones
Rx. of Ochronosis ??
High dose Vit C
Dietary restriction of Phenylalanine & Tyrosine
What is Phenylketonuria ??
A R condition; Phenylalanine metabolism disorder
- Defect: Phenylalanine Hydroxylase (an enzyme that converts Phenylalanine to Tyrosine)
- Deficiency of Tetrahydrobiopterin- deficient cofactor eg.- Secondary to defective Dihydrobiopterin reductase
BOTH leads to high levels of Phenylalanine which cause the c/f
Features of PKU ??
Presents by 6 months eg.- with developmental delay
- Fair hair + Blue eyes
- Learning difficulty
- Seizures (Infantile spasms- typical)
- Eczema
- MUSTY Odour of Urine & Sweat (secondary to PHENYLACETATE, a Phenylketone)
Dx. & Rx. of PKU ??
Guthrie test (heel prick done at 5-9 days of life)
Hyperphenylalaninaemia
Phenylpyruvic acid in Urine
Rx.
- Strict diet prevents learning disabilities (Poor evidence)
- Dietary restriction in Pregnancy as genetically normal fetus may be affected by high maternal Phenylalanine levels
Fruity odour
Garlic odour
Almond smell
Musty body odour
Burnt sugar odour
DKA
Arsenic Poisoning
Cyanide poisoning
Phenylketonuria
Maple syrup urine disease
Name a few X-linked Dominant disorders ??
Alport’s syndrome (85% cases & the rest via A R inheritance)
Rett Disease
Vit D Resistant Rickets
It takes 2 enzymes to synthesize Glycogen
- Glycogen Synthase => creates Alpha 1,4 bonds
After creating, we branch it=>
- Branching Enzyme: creates Alpha 1,6 bonds
Repeat this over & over, we get Glycogen
If Branching enzymes are missing => Long chains of Glycogen : Anderson’s disease
It takes 3 enzymes to breakdown Glycogen
- Glycogen Phosphorylase breaks down Alpha 1, 4 bonds
- De-branching enzyme breaks down Alpha 1, 6 bonds
Final Step is via: G6Phosphatase
Absent Glycogen Phosphorylase in the muscle
- McCardle’s
Absent Glycogen Phosphorylase in the Heart
- Pompeii’s
G Phosphorylase aka Alpha 1,4 Glucosidase
Absence of De-Branching enzyme=> Very short branches branches or Short Chains on Glycogen
- Cori’s
Absent Glucose 6 Phosphatase
- Von-Girke’s
