Lab 4 - Pathomechanisms of Genetic Disorders

Question 1

Pleiotropy

Answer 1

describes genes that have multiple phenotypic effects/ genes that have more than one effect on the body. (Examples: Marfan syndrome, cystic fibrosis)

Question 2

Genetic heterogeneity

Answer 2

production of the same or different phenotypes by different genetic mechanism.

Question 3

Allelic heterogeneity

Answer 3

Describes conditions in which different alleles at a locus can produce variable expression of a disease. Depending on phenotype definition, allelic heterogeneity can cause two distinct diseases, as in Duchenne and Becker muscular dystrophy.

Question 4

Locus heterogeneity

Answer 4

Describes diseases in which mutations at distinct loci can produce the same disease phenotype (examples: osteogenesis imperfecta; retinitis pigmentosa).

Question 5

Expressivity

Answer 5

degree of expression of a gene in an individual/ the degree to which an allele expresses the phenotype.

Question 6

Variable expressivity

Answer 6

A trait in which the same genotype can produce phenotypes of varying severity or expression. (example: neurofibromatosis type 1).

Question 7

Penetrance

Answer 7

The probability of expressing a phenotype, given that an individual has inherited a predisposing genotype. If this probability is less than 1.0, the disease genotype is said to have reduced or incomplete penetrance.

Question 8

Epistais

Answer 8

A gene interaction where one gene masks the phenotypic effect of another gene. Ex. Albinism

Question 9

Polyphenism

Answer 9

The development of multiple, discrete phenotypes from a single genotype by organisms living in different environmental conditions

Question 10

Monogenic

Answer 10

Describing a single-gene, or mendelian, trait

Question 11

Digenic

Answer 11

interaction of two genes

Question 12

Polygenic

Answer 12

Describes a trait caused by the combined additive effects of multiple genes.

Question 13

Loss of heterozygosity

Answer 13

Describes a locus or loci at which a deletion or other process has converted the locus from heterozygosity to homozygosity or hemizygosity.

Question 14

Semidominance (incomplete dominance)

Answer 14

Partial expression of each allele. The expression of each allele is different to that of each homozygous allele.

Question 15

Semidominance in FH

Answer 15

heterozygous individuals are a ‘blending’ or midway point between the homozygous normal individuals (dd) and the homozygous individuals for the mutant allele (DD). The heterozygous (Dd) phenotype is more severe than the normal (dd) phenotype, but less severe than the phenotype seen in ‘DD’ individuals.

Question 16

Familial hypercholesterolemia

Answer 16

• One of the most common autosomal dominant disorders.
• About 1/1,000,000 births is homozygous for the FH gene
• Most homozygotes experience MIs before 20 years of age, and an MI at 18 months of age has been reported. Without treatment, most FH homozygotes die before the age of 30 years
• FH is caused by a reduction in the number of functional LDL receptors on cell surfaces. Cellular cholesterol uptake is reduced, and circulating cholesterol levels increase.
• The number of effective receptors is reduced by about half in FH heterozygotes, and homozygotes have virtually no functional LDL receptors.

Question 17

Genotypes of FH
dd
Dd
DD

Answer 17

Fenotypes
Healthy, no increased risk for MI
MI in middle age (40-50)
MI in childhood

Question 18

Complete dominance

Answer 18

When the phenotype from one allele is always expressed and the phenotype of the second (recessive) allele is always hidden.

Question 19

Complete dominance in Huntington’s disease

Answer 19

caused by a dominant allele.

You only need to inherit one copy of the faulty allele to have Huntington’s disease, unlike cystic fibrosis, where you need to inherit both copies. You can inherit Huntington’s disorder if one or both of your parents carry the faulty allele, because it is a dominant allele.

Huntington disease (HD) affects approximately 1 in 20,000 persons of European descent but is substantially less common in most other populations

interval between initial diagnosis to death is 15-20 y.

affected homozygotes appear to display a clinical course very similar to that of heterozygotes (in contrast to most dominant disorders, in which homozygotes are more severely affected).

Question 20

Symtoms of Huntingston’s disease and age of onset

Answer 20

Symptoms develop between 30-50 y., characterized by a progressive loss of motor control, dementia and psychiatric disorders.
Difficulties in swallowing; aspiration pneumonia is the most common cause of death. Cardiorespiratory failure and subdural hematoma (due to head trauma) are other frequent causes of death.

The area most noticeably damaged is the corpus striatum

Question 21

What kind of repeats causes HD?

Answer 21

CAG tandem repeats

Question 22

Heterozygous inheritance of sickle cell anemia

Answer 22

If you are heterozygous, you have one allele for normal and one allele for the sickle hemoglobin, and produce both shapes of cells –> have sickle cell trait, but no sickle cell symptoms + cannot get malaria.

heterozygous carriers for sickle cell anemia are more resistant toward Plasmodium falciparum, the pathogen that causes tropical malaria. Infected erythrocytes rapid destroyed, and sickle shaped cells cannot carry oxygen –> parasite cannot survive

Question 23

The ABO gene on which chromosome determines the blood groups of the ABO system?

Answer 23

chromosome 9q34

Question 24

Which enzyme do allele A and allele B code for, and what is the function?

Answer 24

glycosyltransferase. Takes part in the glycosylation of proteins in the cell membrane.

Question 25

What does GTA (coded by allele A) and GTB (coded by allele B) transfer to the carbohydrate chain?

Answer 25

GTA: N-acetylgalactose (GalNAc)
GTB: galactose (Gal)

Question 26

Blood group AB

Answer 26

compound heterozygous for alleles A and B (genotype AB) modify some of their glycoproteins with GalNAc and others with Gal.

Question 27

What kind of mutation has allele O?

Answer 27

Frameshift deletion

Question 28

Which blood groups are dominant over blood group O?

Answer 28

A and B.

Question 29

What kind of disease is OI?

Answer 29

genetically heterogenous disease of the connective tissue.It is a disorder of the calcified as well as soft connective tissues.

Question 30

What is OI caused by=

Answer 30

deficiency or abnormal production of collagen 1.

Question 31

On which chromosomes are pro collagen COL1a1 located and COL1A2 located?

Answer 31

COL1A1: chromosome 17
COL1A2: chromosome 7

Question 32

Mutation, genes, copies that gives rise to mild phenotype of OI type 1. How much reduction of collagen synthesis

Answer 32

Null mutation –> complete loss of one of the 2 copies of either COL1A1 or COL1A2. 50% reduction of collagen synthesis

Question 33

What kind of mutation leads to OI type 2?

Answer 33

point mutation. gives rise to abnormal but stable protein integrated into the pro collagen triple helix along with normal protein. Mutated protein affects the function of a normal protein –> more severe clinical picture –> Negative effect

Question 34

Clinical features of OI

Answer 34

• perinatal lethal type
• disproportionate short stature due to abnormally short, fractured, and bent extremities.
• torso of normal length, but narrow chest because of multiple rib fractures (pearl-string ribs)

Question 35

Mutations in which gene on which chromosome causes Marfan syndrome?

Answer 35

fibrillin-1 (FBN1) gene on chromosome 15q.

Question 36

What kind of mutations causes Marfan syndrome?

Answer 36

1/4: de novo
70%: missense
Also deletions of FBN1

Question 37

Symptoms and signs of Marfan syndrome

Answer 37

Tall stature, arachnodactyly, pectus carinatum, pectus excavatum, scoliosis, pes planus, pneumothorax, atrophic striae of the skin, lumbosacral dural ectasia –> lower back pain, genital and rectal pain, and numbness in the lower extremities.
Facial features: dolichocephaly, enophtalmos, downslanting palpebral fissures, malar hypoplasia and retrognathia.

Question 38

Progeria syndrome

Answer 38

group of disorders that cause rapid aging in children. monogenic disorders.

Question 39

Mutation on which gene is responsible for Werner syndrome (progeria adultorum)? Which family does it belong to, and what is it required for?

Answer 39

WRN gene. Belongs to DNA helicases, required for DNA replication, recombination, chromosome segregation, DNA repair, transcription, unwinding of DNA.

Hindered DNA repair, increased telomere shortening, and increased genomic instability all may contribute to premature senescence in Werner Syndrome.

Question 40

Symptoms of Werner syndrome

Answer 40

At the age of 20, most of the patients have gray hair with progressive atrophy and hardening of the skin, premature development of cataract, osteoporosis, diabetes mellitus, and varying degrees of atherosclerosis.
The average life expectancy is 47 years. The most frequent causes of death are myocardial infarction and malignant.

Question 41

When does children with Hutchinson-Gilford syndrome begin to show symptoms of premature aging, and which gene is affected?

Answer 41

First year of life, LMNA gene.

Question 42

Which amino acids are found in high content in the polypeptides of OI?

Answer 42

glycine, proline and hydroxyproline. Every third position in the polypeptide sequence is occupied by glycine.