CPR1 - Genetics {1.07,2.04,2.07,2.14}

What genes encode for spectrin proteins?

SPTA1 and SPTB

How are SPTA1 mutations typically inherited in hereditary spherocytosis?

Autosomal recessive

How are SPTB mutations typically inherited in hereditary spherocytosis?

Autosomal dominant

What gene encodes for ankyrin?

ANK1

What is the function of ankyrin?

adapter protein that links spectrin to AE1 (band 3)

What gene encodes for AE1 (Band 3)?

SLC4A1

What is the function of AE1 (band 3)?

Cl-/HCO3- antiporter/membrane structural support

What gene encodes for protein 4.2?

EPB42

What is the function of protein 4.2?

Regulate interaction between ankyrin and AE1

What is the pathophysiology of hereditary spherocytosis (HS)?

Vertical defects of membrane structural integrity leading to spherical cells, removed from circulation and destroyed by spleen

What is the clinical presentation of hereditary spherocytosis (HS)?

Splenomegaly, juandice, decreased haptoglobin, increased indirect bilirubin, increased serum LDH, erythroid hyperplasia, Increased MCHC

What is hereditary elliptocytosis (HE)?

Specific mutations (SPTA1 and SPTB) cause a failure of spectrins to form tetramers

What are Heinz bodies seen in?

G6PD deficiency, caused by aggregation and precipitation of oxidized Hb

Why are RBCs the only cells apparently affected by G6PD deficiency?

Most other cells have a backup enzyme for making NADPH, Malic Enzyme (ME)

What does the mutation G6PD^A- cause?

Decreased stability of the G6PD protein without impaired enzyme activity

What does the mutation G6PD^B- cause?

Decreased stability of the G6PD protein with impaired enzyme activity

What gene is mutated in pyruvate kinase (PK) deficiency?

PKLR

What is the result of pyruvate kinase (PK) deficiency?

Results in up to half the amount of ATP produced, severe osmotic imbalance, decreased affinity to O2

What is the pathophysiology of pyruvate kinase (PK) deficiency?

Backup ahead of PK increases 2,3-BPG decreasing Hb O2 affinity and increasing O2 release to tissues

What gene is mutated in Sickle cell disease (SCD)?

HBB

What triggers hemolysis in G6PD deficiency?

Infections, oxidative drugs (sulfa drugs), Fava beans

What is the pathophysiology of sickle cell disease (SCD)?

Introduction of Val creates hydrophobic pocket that allows mutated Hb to polymerize into filaments after deoxygenation

How is von Willebrand disease inherited?

Autosomal dominant

What is the normal function of vWF is coagulation?

Anchors platelets to subendothelial collagen by binding to GP1b, binds factor VIII and protects it from degredation

What will insufficient vWF impair?

Both platelet plug formation and the coagulation cascade

What post-translational modification does vWF receive?

glycosylation, assembly into dimers in ER, multimerization in golgi

Where is vWF stored?

Weibel-palade bodies (WPBs)

What is the relationship between size and binding capacity of vWF?

Larger structural units of vWF have a higher GPIb binding capacity

What enzyme keeps tabs on vWF?

ADAMTS13

What is the function of ADAMTS13?

Cleaves vWF in circulation to avoid excessive blood clotting

What is thrombotic thrombocytopenic purpura (TTP)?

ADAMTS13 deficiency causing microangiopathic hemolytic anemia, thrombocytopenia, neurological symptoms

What is vWD type I characterized by?

10-45% of normal vWF made

What is vWD type II characterized by?

Normal amount, but defective vWF made

What is vWD type III characterized by?

<10% detectable vWF protein

What is the pathophysiology of vWD?

Impaired platelet plug formation, impaired coagulation cascade (reduced factor VIII→impaired tenase→decreased X to Xa and thus II→IIa)

What is Ristocetin-induced platelet agglutination (RIPA)?

Ristocetin changes vWF so that it binds more tightly to GPIb stimulating platelet aggregation

What does failed or reduced platelet aggregation indicate in a Ristocetin-induced platelet agglutination?

vWF issues or a deficiency of GPIb

What is hemophilia A?

X-linked recessive factor VIII deficiency

What is hemophilia B?

X-linked recessive factor IX deficiency

What is Hemophilia C?

Autosomal recessive or dominant factor XI deficiency

What are acute forms of leukemia associated with?

Block in proper differentiation of leukocyte precursors, with release of large numbers of blasts into circulation

What are chronic forms of leukemia associated with?

Unregulated proliferation of mostly mature/differentiated cells

What is chronic myeloid leukemia characterized by?

Appearance and creation of the philadelphia chromosome between BCR and ABL1

What is the etiology of chronic myeloid leukemia?

Translocation occurs in a single HSC in bone marrow (somatic mutation not inherited), mutant tyrosine kinase signals in perpetuity causing uncontrolled cell proliferation, WBC counts grossly elevated

What is the treatment of choice for chronic myeloid leukemias?

Imatinib, specifically targets mutant tyrosine kinase

What is the key translocation seen in chronic myeloid leukemia?

t(9;22)(q34;q11), BCR-ABL1 fusion protein

How can chronic myeloid leukemia be detected?

Karyotype, FISH, RT-PCR

What is chronic lymphocytic leukemia with deletion of chromosome 13q14 characterized by?

Encodes for miRNAs that regulate expression of specific transcripts, deletion associated with relatively benign disease

What is chronic lymphocytic leukemia with trisomy 12 characterized by?

Increased expression of MDM2 a protein that inhibits p53

What is chronic lymphocytic leukemia with deletion of chromosome 11 characterized by?

Disrupted ATM gene, protein responds to double stranded DNA breaks, poor prognosis

What is chronic lymphocytic leukemia with deletion of chromosome 17 characterized by?

Directly disrupts TP53 (p53), very poor prognosis

What is the function of BCL-2 in the cell?

Inhibits apoptosis

What is commonly upregulated/overexpressed in chronic lymphocytic leukemia?

BCL-2

What is the function of ATM in the cell?

Binds to double stranded breaks and phosphorylates Chk2

What is the function of Chk2 in the cell?

Phosphorylates p53

If DNA damage is mild what will p53 do?

Stimulate expression of CDK inhibitor proteins like p21 causing cell cycle arrest until damage can be repaired

If DNA damage is severe what will p53 do?

Stimulate transcription of pro-apoptotic proteins such as PUMA

What is the central problem in acute myeloid leukemia?

Accumulation of abnormal precursor cells in bone marrow precludes the production of normal marrow cells

What is Fanconi anemia at increased risk for?

AML, defects in interstrand cross link repair

What are patients with Bloom syndrome at higher risk for?

AML and ALL, DNA helicase gene mutation

What are patients with Ataxia Telangiectasia at higher risk for?

ALL, ATM gene defect→impaired double strand break repair

What are patients with Li-Fraumeni syndrome at higher risk for?

AML and ALL, germline mutations in TP53

What are patients with trisomy 21 (down syndrome) at higher risk for?

AML and ALL

What drug has shown promise in many AML patients?

Vorinostat, relieve inhibition of transcription

What is acute promyelocytic leukemia?

Subtype of AML, chromosome 17 involved, disruption of retinoic acid receptor-α (RARα)

What is the function of RARα?

Stimulates the differentiation of promyelocytes into granulocytes

What is the fusion protein seen in APL?

PML + RARα, failure of cells to differentiate, instead proliferate and undergo clonal expansion

What can issues associated with APL be overcome with in some cases?

RA (ATRA), synthetic form of retinoic acid

What is acute lymphoblastic leukemia caused by?

Hyperproliferation of lymphoid progenitors, affected cells feature T and B cell progenitor characteristics

What characteristic cytogenic changes have been noted in ALL?

Changes in numbers of individual chromosomes

When is hyperdiploidy (>50 chromosomes) seen in ALL?

Often in childhood ALL, associated with favorable prognosis

When is hypoploidy (<46 chromosomes) seen in ALL?

Rare, associated with very poor prognosis

What is the difference between Philadelphia chromosomes seen in ALL compared to CML?

Translocation propagates in the lymphoid lineage, different/shorter BCR-ABL fusion protein that is more pathogenic

What fusion proteins are seen in ALL?

TEL-AML1, BCR-ABL, E2A-Pbx1, E2A-HLF, MLL-AF4

What deletion can be seen in ALL?

p16INK4a

What can be overexpressed in ALL?

c-Myc-IgH

What does BCR-ABL fusion proteins seen in ALL need to be treated with?

Chemotherapy + TKI

How can CAR-T cells treat ALL?

CAR T-cells grown in lab, should recognize and destroy cancer cells based on cell surface markers (CD19)

What chromosomal change creates the TEL-AML1 fusion protein in ALL?

t(12;21)(p12;q22)

What chromosomal change creates the BCR-ABL fusion protein in ALL?

t(9;22)(q34;q11)

What chromosomal change creates CDKI deletion in ALL?

9p21 deletion

What chromosomal change creates the E2A-Pbx1 fusion protein in ALL?

t(1;19)(q21;p13)

What chromosomal change creates the E2A-HLF fusion protein in ALL?

t(17;19)(q21;p13)

What chromosomal change creates the MLL-AF4 fusion protein in ALL?

t(4;11)(q21;q23)

What chromosomal change creates the c-Myc-IgH fusion protein in ALL?

t(8;14)(q24;q32)