Ch. 12 Molecular, Biochemical and Cellular Basis of Genetic Diseases

Diseases involving enzymes:

What is meant by housekeeping proteins?  Describe how they are generally expressed

a.         Role is to maintain cell structure and function

b.         They are present in every cell

c.         Clinical effects of mutations in these proteins are limited to a few tissues

d.         Genetic redundancy

• redundant genes ensure housekeeping proteins are always available

Aminoacidopathies:

What are the 6 categories of Diseases involving Enzymes?

a.         Aminoacidopathies (ex: PKU)

b.         Lysosomal Storage Diseases (ex: Tay Sachs)

c.         Altered protein function due to abnormal post-translational modification (ex: I-cell disease)

d.         Loss of protein function due to impaired binding or metabolism of cofactor (ex: BH4 and Phenylalanine hydroxylase)

e.         Mutations of an enzyme inhibitor (ex: alpha-antitrypsin deficiency)

f.            Dysregulation of biosynthetic pathway (ex: acute intermittent)

Aminoacidopathies:

Describe what is meant by an enzymopathy. What is an aminoacidopathy?

a.         Enzymopathies – pathophysiology related to accumulation of substrate or deficiency of product

• Almost always recessive or X-linked

b.         Single gene defect may cause loss of function of more than one enzyme

Aminoacidopathies:

Generally, describe Classic Phenylketonuria. (aminoacidopathies)

a.         Mutation in the gene encoding phenylalanine Hydroxylase (PAH) which converts phenylalanine to tyrosine

• PKU is near complete absence of PAH and causes neurological damage due to excess phenylalanine BUT can be minimized by reducing dietary intake

b.         Defects in Tetrahydrobiopterin (BH4) metabolism is a cofactor for PAH

• Converts PKU to tyrosin

Aminoacidopathies:

How is allelic heterogeneity demonstrated in some cases of PKU?

autosomal recessive

Aminoacidopathies:

How is locus heterogeneity demonstrated in some cases of PKU?

  Locus heterogeneity – proteins coded by multiple loci involved in disease act at different steps in a single biochemical pathway

Aminoacidopathies: 

Describe the general strategy for treatment of enzymopathies.

Provision of increased amount of cofactor = enhance activity of residual enzyme

• Cofactor is BH4

What are lysosomes?  Generally, describe lysosomal storage disorders.

a.         Lysosomes – organelles containing hydrolytic enzymes where biological macromolecules are degraded

b.         Related diseases are result of substrate acclamation and characterized by unrelenting progression

c.         Autosomal recessive

What are effective strategies for treating lysosomal storage disorders?

Bone marrow transplant and enzyme replacement therapy improve prognosis

Describe the lysosomal storage disorder Tay Sachs disease.  What population is mostly affected?

a.         Body’s inability to degrade GM2 gangliosidases due to marked deficiency of hexosaminidase A (Hex A)

b.         Impacts the brain – infants will appear normal till age 3-6 months and experience progressive neurological deterioration until death between 2-4

c.         Common among Ashkenazi Jewish population where 1:27 are carriers

Diseases involving enzymes: Altered Protein Function due to Post-translational Modification

Loss or gain of glycosylation belong in what category of Diseases involving enzymes?

Post translational modification

Diseases involving enzymes: Altered Protein Function due to Post-translational Modification

What is the major problem with the loss of glycosylation affecting acid hydrolases?  Describe an associated disease. Describe the effects of gain of glycosylation

Usually, lysosomal acid hydrolases are directed to their location by post-transcriptional modification but in cases of I-Cell Disease, levels of acid hydrolases are diminished and found in excess body fluids

• Causes skeletal changes, growth retardation, intellectual disabilities and survival is less than 10 years

Diseases involving enzymes: Altered Protein Function due to Post-translational Modification

Generally, describe homocystinuria and its cause.

Altered Protein function due to post-translational modification

Homocystinuria – body’s inability to break down amnio acid methionine due to cystathionine synthase deficiency (impaired cofactor binding = altered conformation)

• Autosomal recessive

Mutations and Enzyme Inhibitors:

Describe alpha1-antitrypsin deficiency syndrome and its cause.  Explain why it is described as a conformational disease?

a.         Autosomal recessive

b.         Deficiency of alpha1 at protein, a protease inhibitor that inhibits proteases including elastase in lungs

• Lung disease association

c.         Confirmational disease – mutation causes the shape/size of protein to change, predisposed to self-association and tissue deposition

•   A1AD is due to misfolding of protein

Dysregulation of biosynthetic pathway:

Describe the genetic and physiological cause of acute intermittent porphyria

a.         Autosomal Dominant

b.         Deficiency of porphobilinogen (PBG) deaminase – part of the biosynthetic pathway for heme and required for Hgb and drug metabolizing enzymes

Defects in protein receptors:

Describe the most common genetic cause of familial hypercholesterolemia and the general physiology of the disease.

Autosomal. Semi-dominant – manifests earlier and more severely in homozygotes

• 1 of most common single-gene disorders

Due to mutations on the LDL receptor (LDLR) gene

Defects in protein receptors:

Generally describe the 6 classes of LDLR mutations

a.         Class 1: null alleles, the most common disease-causing mutations at this locus; have no receptors

b.         Class 2: Transport-deficient – receptors made but are not in the correct location

c.         Class 3: incapable of binding LDL (cell won’t bind to receptor)

d.         Class 4: Impair localization of the receptor so LDL can’t enter the cell (can’t pull LDL into cell)

e.         Class 5: recycling defective – receptor is degraded

f.            Class 6: Defective targeting – reduces endocytosis

Defects in protein receptors:

Generally describe the genetic cause and physiology of cystic fibrosis.

a.         CF is caused by mutation on the CFTR gene which regulates chloride channel in the membrane

• Abnormal fluid and electrolyte transport results in increased Cl- and Na+ concentrations in sweat and a depletion of airway surface liquid in the lungs

• More than half of CF mutations are missense substitutions

b.         Most fatal autosomal recessive disorder in white populations

Defects in protein receptors:

Generally describe the 6 classes of CFTR mutations.

a.         Class 1: Null alleles – no CFTR proteins made

b.         Class 2: Impaired folding of CFTR protein

c.         Class 3: normal delivery to cell surface but disrupted function

d.         Class 4: defective chloride ion conduction

e.         Class 5: reduce number of CFTR transcripts

f.            Class 6: synthesized normally but unstable at cell surface

Disorders of Structural protieins

What is the general function of the dystrophin protein in the body?

a.         Stabilizes the myofiber membrane and allows Ca+ into the cell without complications

Disorders of Structural proteins:

Describe the general differences between Duchenne and Becker Muscular Dystrophy

a.         DMD – X linked mutation; progressive muscle wasting with individuals in the wheelchair by 12

• Genetically lethal (fitness = 0 – can’t reproduce)

b.         Becker – Also a mutation on the dystrophin locus but still expresses some dystrophin

• Fitness= 70% (can reproduce)

• Milder phenotypes – still walking at 16

Disorders of Structural proteins:

1. Generally describe osteogenesis imperfecta.  What protein is mainly the cause of OI?

2. What is the difference between Type I OI and Types II-IV?

1.   Osteogenesis imperfecta (OI) – group of inherited disorders that predispose to skeletal deformity and easy fracturing

• Clinical variation by allelic and locus heterogeneity

2.   Type 1 diminished collagen production and type 2-4 are defective collagen

Neurodegenerative Diseases

What are the 3 main hypotheses concerning the causes of Alzheimer’s Disease?

a.         Complex involving 1 or more multiple incompletely penetrant genes that act independently

b.         Multiple interacting genes

c.         Combo of genetic and environmental factors

Neurodegenerative Diseases

Generally describe the gene suspects for Alzheimer’s

a.         APOE gene, Presenilin 1 and 2 are possible cofactors for gamma-secretase (enzyme that cleaves BAPP to form AB42) Epsilon 4 is a major risk factor, TREM2 – 2^nd most common contributor to late onset

Diseases of mtDNA

What is replicative segregation and how are homoplasy and heteroplasmy associated?

a.         Replicative segregation – multiple copies of mtDNA in each mitochondria replicate and sort randomly among newly synthesized mitochondria which are randomly distributed between daughter cells

b.         Homoplasmy is when cells all have the same mitochondria (sorted to be the same)

c.         Heteroplasmy is when cells have different mitochondria

1. Why is mtDNA much more prone to mutation that nuclear DNA?

2. What factors generally characterize mtDNA diseases?

1. Because of oxidative process

2. Neuromusclar conditions + Deletions, mutations in tRNA and mRNA (non-coding genes)

Describe phenotypic threshold in regard to mtDNA disease?

a.         Phenotypic threshold is the threshold in the proportion of mtDNA carrying the mutation that must be exceeded for clinical disease to become apparent in affected tissue

• Produces variability so it explains why individuals that carry mtDNA diseases may not show the phenotype – threshold is not met

List 5 mtDNA diseases

a.         Leber Hereditary Optic Neuropathy

b.         Leigh syndrome

c.         MELAS

d.         Deafness

e.         Kearns-Sayre Syndrome (KSS)

Diseases due to expansion of unstable repeat sequences:

List two diseases caused by repeat sequence expansion that affect coding regions.  List two diseases caused by repeat sequence expansions of non-coding regions.

Coding regions: Huntington’s disease and Spinocerebellar ataxis

Non-coding regions: Fragile X syndrome, Friedrich Ataxia, and Myotonic Dystrophy1

Diseases due to expansion of unstable repeat sequences:

Describe 3 classes of Diseases due to the expansion of unstable repeat sequences, an example of a disease in each category, and a description of each disease.

a.         Class 1: loss of protein expression (Fragile X) – expansion of CGG in the FMR1 gene leading to excessive methylation of cytosines in promoter

b.         Class 2: expansions of noncoding repeats (CTG) (Myotonic Dystrophy) – autosomal dominant and most pleiotropic phenotype of entire class

• Considered a spliceopathy – RNA binding proteins normally involved in splicing are sequestered by the repeated sequences

c.         Class 3: CAG repeats (Huntington’s) – protein damages neurons and produces neurodegeneration