Biochemical Genetics, Autosomal Dominant Disorders

Question 1

What are the gene level sites where mutations can occur?

Answer 1

In the coding region (missense, nonsense), promoter regions, RNA splicing defects, 5’ cap site mutations, 3’ polyA defects, frameshifts, deletions, and fusion proteins.

Question 2

How can mutations in various gene sites affect the normal gene product?

Answer 2

Can get changes in important chromosomal proteins, membrane transport proteins, structural proteins, regulatory proteins, catalytic proteins, and cell surface recognition proteins.

Question 3

Why are some biochemical mutations not deleterious?

Answer 3

Degeneracy of the genetic code, amino acids are often unnoticed, different AA in the “non-business” area of a protein doesn’t markedly influence function. and man is diploid for autosomal genes and has multiple alleles for each protein.

Question 4

How many lethal genes do you have in your genome?Why are you still alive?

Answer 4

6-10 on average. But, you are protected because of your two alleles.You are alive because you are diploid. Keep it up.

Question 5

What are the five situations” that a single mutated allele might cause a dominant disorder?”

Answer 5

When the gene codes for….1. A structural protein, all of which is necessary for normality, or when it is part of a multimeric protein (collagen and osteogenosis imperfecta)2. A regulatory protein (Waardenburg syndrome)3. An inducer of growth and development and whose function depends only on amount4. An enzyme that acts to capacity5. When the gene product causes the protein to take on a new function (Huntington’s)

Question 6

What are the characteristic features of autosomal dominance inheritance?

Answer 6

non gender specific1/2 of individuals in a family have itmost disorders do not effect reproductive fitnessvertical pedigree with effected individuals in all generations

Question 7

Why are autosomal dominant disorders in general less lethal than other inherited disorders?

Answer 7

If they were particularly lethal as well as dominant, they would have died out (not have had a chance to be transmitted).This implies that AD diseases aren’t magically less lethal than AR diseases– just that the lethal AD mutations don’t reproduce successfully (thus have no pedigree).

Question 8

Why do autosomal dominant disorders show such a variable phenotype even within families?

Answer 8

Unknown interactions between the rest of the genome and the environment. Super.

Question 9

What factors may complicate the assessment of an autosomal dominant pedigree?

Answer 9

Different penetrance and expressivity.

Question 10

What is the difference between penetrance and expressivity, and between genocopy and phenocopy when describing an inherited disorder.

Answer 10

Penetrance: The frequency with which a disease may be detected if the gene is present.A mutant gene may not always be phenotypically expressed.Expressivity: The range of clinical problems resulting from a mutant gene, from mild to severe.Genocopy: genetic disorders in two different alleles = similarPhenocopy: A syndrome caused by environmental factors that mimics a genetic disease.

Question 11

What are the characteristic features and molecular basis of Achondroplasia?

Answer 11

Most common dwarfism 1/15,000 births80% of mutations are new mutations (in sperm/egg)Everyone who has disease has exact same mutation: transmembrane domain of FGF-R3 - GC pair –> AT (deamination of C), product is functional 100% doesn’t need cofactor. Normally shuts off chondrocyte proliferation.Paternal age effect. Fathers > 40 = 3x more than 20.

Question 12

What are the characteristic features and molecular basis of Marfan Syndrome

Answer 12

Tall, long arms + fingers, scoliolis, detached retina, dislocated lens, cardiovascular problem = death = aortic root enlargment (weak). Reduced penetrance.Defect in fibrillin, provides scaffolding for elastin (which allows vasculature to be flexible).TGFßR2 fail gives Marfan phenotype presentation. More cardiovascular defects, but no ocular problems.

Question 13

What are the characteristic features and molecular basis of Neurofibromatosis-I

Answer 13

Characterized by having 6 or more birth marks (cafe ole’ spots). Long bones, subcutaneous neurofibromas that line the nerves + invade nervous system and give rise to new cancers. Reduced fitness (50%)1/2 are new mutations. 100% penetrant.Neurofibromin is a GAP (GTPase activating) protein. Tumor supressor.

Question 14

What are the characteristic features and molecular basis of Huntington Disease

Answer 14

Late onset. Appears after individual passes reproductive time. Only 30% know by time of 30.Due to loss of brain tissue in basal ganglia. Triplet repeat disorder. Juvenile anticipation.

Question 15

What are the characteristic features and molecular basis of Alzheimer Disease?

Answer 15

Tends to show early-onset Alzheimer’s. Notice that the great majority of Alzheimer’s is sporadic.Amyloid plaques, remember?

Question 16

What is a paternal age effect?

Answer 16

Increased frequency of inheriting disease gene when father is over 39 years old.

Question 17

What is a compound heterozygote?How is this related to the variable phenotype of many autosomal recessive disorders?

Answer 17

Most recessive mutants are probably heterozygotes for two different mutant alleles, and therefore display variable severity.

Question 18

Compare dominantly and recessively inherited diseases in terms of their mutant gene products. Understand when a particular mutation will be expressed in a dominantly inherited fashion.

Answer 18

Recessively inherited diseases: need both genes to be bad before a disease phenotype crops up.Dominantly inherited diseases: only need one bad copy of a gene to produce disease or death.Dominant inherited disease mutations tend to be in genes coding for:structural, regulatory proteins, proteins that induce growth and enzymes.Recessive disease mutations tend to be present in genes coding for proteins that are normally present at a surplus level in cells.

Question 19

What problems do late-onset disorders create for genetic counseling?

Answer 19

since disease may not have shown by the time the parents want to have children, may not be able to counsel them accurately on the genetic risks posed to their offspring.Or, the children could still have many long happy years before onset of disease (Huntington’s).