Genetics Chapter 13

oxidizes the critical methionine residure at the active site of alpha1-antitrypsin (alpha1AT), reducing its ability to inhibit elastase by 2000 fold. This creates a phenocopy of alpha1AT deficiency.

1.) Congenital heart defects
2.) Cleft Lip and Pallate
3.) Pyloric Stenosis

1.) gene not identified or pathogenesis not understood.
2.) Prediagnostic fetal damage
3.) severe phenotypes are less amenable to intervention (and first presenting)

Although diet prevents the onset of mental retardation, intelligence levels are diminished.

inability to metabolize galactose, a component of lactose (milk). individuals lack galactose-1-phosphate uridyltransferase. (GALT)

catalyzes the conversion of galactose 1 phosphate to uridine diphosphogalactose.

Galactosemia.

usually normal at birth but develop gatrointestinal problems, cirrhosis of the liver, and cataracts in the weeks after introduction to milk.

Removal of affected eye.

increased susceptibility to neoplam formation after the first decade.

Adding foreign clotting factor can create antibodies which destroy the bodies already diminished supply.

Hemophilia.

Iron overload - this is treatable by using chelating agents.

You must also know if the condition is caused by the phenylalanine hydroxylase (PAH) gene itself or if the condition is in the synthesis of its cofactor tetrahydrobiopterin (BH4)

phenylalanine is essential for protein synthesis.

ARI DDD

Avoidance
Dietary Restriction
Replacement
Diversion
Inhibition
Depletion

SPSPSCTBAE

Supportive (30%)
Product Replacement (20%)
Substrate Limitation (20%)
Pharmacological Intervention (10%)
Surgery (4%)
Cofactor Supplementation (4%)
Tissue Transplantation (4%)
Bone Marrow Transplantation (3%)
Alternate Pathway (3%)
enzyme replacement/gene therapy (1%)

Hyperphenylalanemia: Phenylalanine

Galactosemia: Galactose

Congenital hypothyroidism - Thyroxine

Biotinidase Deficiency - Biotin

Urea cycle disorders (nitrogen poisoning) - Sodium Benzoate (glycine pathway)

Familial hypercholesterolemia (heterozygotes only) - Addition of resins that bind bile salts to digest them. also drugs that block intestinal absorption of bile acids. (drives creation of new bile acids which require lipids)

convert ammonia which is neurotoxic to urea which is benign and excretable.

hyperammonemia (urea cycle)

It binds with glycine to form hippurate which is excreted in the urine.

in order to replace the glycine, ammonia is consumed.

cholestyramine

inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate limiting enzyme of cholesterol synthesis.

two drugs working in tandem create a greater result. (example cholestyramine and statins)

LDL apheresis (direct removal of LDL from plasma.)

hundreds to thousands of AMU

Vitamin B6 supplements. (vitamin B6 is pyridoxine, the precursor of pyridoxal phosphate neccesary to alleviate a deficiency in cystathionine synthase)

the delta508 mutation causes misfolding which is recognized by a calcium dependent chaparone protein and degraded in the Endoplasmic reticulum

curcumin, a nontoxic mixture of compounds in tumeric, inhibits a calcium pump in the ER, thereby preventing the binding of the calcium dependent chaparone to the mutant delta 508 cystic fibrosis protein.

Premature stop codon

encourages translational apparati to skip over the premature stop codon, and instead translate an Amino acid with a similar codon. (Treats cystic fibrosis)

Nasal epithelial cells.

factor VIII is added to plasma during blood transfusion

frequency of treatment
available supply
immune response

immune response. (B and T cell immunity deficiency) due to accumulation of toxic purines.

Bone Marrow transplant although gene therapy exists. Bovine versions of the protein also work well.

1.) less susceptible to antibody response
2.) longer half life
3.) remains in the extracellular fluid, so it will degrade excess purines.

Gaucher Disease and Fabry Disease

(research in 6 others)

lysosomal storage disorder affecting 1/450 ashkanazi jews and 1/40000 to 1/100000 in other populations. Autosomal recessive. deficiency of glucocerebrosidase.

enzyme which degrades glucocerebroside in the lysosome of macrophages.

deficiency results in Gaucher Disease and an enlargement of the Liver and Spleen. Bone marrow is replaced by lipid laden macrophages called "Gaucher cells".

lipid laden macrophages resulting from accumulation of glucocerebrosides in Gaucher disease. These cells replace bone marrow and compromise creation of erythrocytes and platelets. this results in anemia and thrombocytopenia and bone lesions.

1.) Does not involve the CNS
2.) Alternative is high risk bone marrow
3.) Protein is available in abundance.
4.) the macrophage is well understood to target an enzyme to it.

increasing the amount of mRNA transcribed from the normal or functional allele.

Autosomal Dominant

the gene encoding complement 1 esterase inhibitor.

long term prophylaxis with attenuated androgens, particularly danazol.

fetal hemoglobin Hb F

incorporation of cytidine analogues (decitabine) are incorporated into the DNA instead of cytidine which inhibits methylation of CpG repeats in the 5' promotor region.

RNAi

Huntingtons - Toxic protein

Osteogenesis Imperfecta - Defective protein.

The cells maintain the genetic composition of the donor.

homozygous familial hypercholesterolemia

(a1AT deficency) is also also showing promise

1.) ability to proliferate to form the differentiated cell types of tissue in vivo
2.) ability to self renew--to form a new stem cell.

Cloning

the use of embryonic stem cells generated by nuclear transplantation to form differentiated cell types of the body in culture

reimplanting an embryo obtained by nuclear transplantation into the uterus of a surrogate mother.

hematopoetic stem cells and corneal stem cells

10% (a lot)

1.) implanted cells replace existing cells.
2.) enzyme from implanted cells is released and accepted by a recipient cell.

1.) Allogenic donor cells
2.) patients won bone marrow cells transduced with the normal gene encoding the enzyme which is mutant in the patient

Bone Marrow

Cause: deficiency of galactocerebrosidase
Symptoms: relentless degeneration of central and peripheral myelin, spasticity, dementia, and peripheral neuropathy

Treatment: bone marrow transplant

1.) recipients are more tolerant of histoincompatible blood than of other allogenic donor cells

2.) wide availability of cord blood

3.) risk of graft vs host disease is substantially reduced.

there is a time dependence to treatment. Placental blood is readily available in comparison to bone marrow which can take a long time to locate a donor.

live transplant

1.)mortality after transplant is significnat

2.) finite supply of organs (cord blood is an exception)

Severe combined immunodeficiency

recombination brings with it a large risk of deletion/insertion mutations

stable nuclear but nonchromosomal piece of DNA

Similar to to the adenovirus.

long lived cells such as neurons, myocytes and hepatocytes

Recombination effects could remove CAG repeats. or the dominant allele entirely.

PKU could be treated by implanting phenylalanine hydroxylase into bone marrow cells which would function as the normal enzyme in a new location

1.) retrovirus
2.) adenovirus
3.) adeno-associated virus

8kb

the cell must replicate in order to incorporate the material. this limits use in neurons.

the class of viruses that include HIV, which are capable of incorporating DNA into slowly dividing cells.

Benefits: no adverse effects on humans, can be obtained at high titer

Disadvantage: only can hold up to 5kb. Associated with a death due to immune response in clinical trials.

1.) Naked DNA: cDNA or siRNA
2.) DNA packaged in liposomes
3.) protein-DNA conjugates
4.) artificial chormosomes

1.) immune response
2.) malignant neoplasms due to insertional inactiation of tumor supressor genes
3.) insertional inactivation of essential genes.

mutations in genes required for lymphocyte maturation. Patients lack B and T lymphocytes and early death is common.

X linked SCID is particularly caused by the loss of a gene encoding the gamma c-cytokine receptor.

1.) restoration of the receptor form bone marrow studies demonstrates pathophysiological potential

2.) transduction would create a selective advantage over untransduced cells (testable)

Development of lymphocytosis and leukemia due to insertion by the retroviral vector inot LMO2.

T cell accumulation and leukemia.

photoreceptor degenerative disease, leading to blindness.

more than 10 genes, but the RPE65 gene is the current focus

cycling of retinoids (vitamin A metabolites) to photoreceptors

large size of cDNA needed and the need to incorporate the gene into a massive number of myocytes.

dystrophin

Factor IX

Very