Lab 4 - Pathomechanisms of Genetic Disorders Flashcards
Pleiotropy
describes genes that have multiple phenotypic effects/ genes that have more than one effect on the body. (Examples: Marfan syndrome, cystic fibrosis)
Genetic heterogeneity
production of the same or different phenotypes by different genetic mechanism.
Allelic heterogeneity
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.
Locus heterogeneity
Describes diseases in which mutations at distinct loci can produce the same disease phenotype (examples: osteogenesis imperfecta; retinitis pigmentosa).
Expressivity
degree of expression of a gene in an individual/ the degree to which an allele expresses the phenotype.
Variable expressivity
A trait in which the same genotype can produce phenotypes of varying severity or expression. (example: neurofibromatosis type 1).
Penetrance
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.
Epistais
A gene interaction where one gene masks the phenotypic effect of another gene. Ex. Albinism
Polyphenism
The development of multiple, discrete phenotypes from a single genotype by organisms living in different environmental conditions
Monogenic
Describing a single-gene, or mendelian, trait
Digenic
interaction of two genes
Polygenic
Describes a trait caused by the combined additive effects of multiple genes.
Loss of heterozygosity
Describes a locus or loci at which a deletion or other process has converted the locus from heterozygosity to homozygosity or hemizygosity.
Semidominance (incomplete dominance)
Partial expression of each allele. The expression of each allele is different to that of each homozygous allele.
Semidominance in FH
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.
Familial hypercholesterolemia
- 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.
Genotypes of FH
dd
Dd
DD
Fenotypes
Healthy, no increased risk for MI
MI in middle age (40-50)
MI in childhood
Complete dominance
When the phenotype from one allele is always expressed and the phenotype of the second (recessive) allele is always hidden.
Complete dominance in Huntington’s disease
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).
Symtoms of Huntingston’s disease and age of onset
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
What kind of repeats causes HD?
CAG tandem repeats
Heterozygous inheritance of sickle cell anemia
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
The ABO gene on which chromosome determines the blood groups of the ABO system?
chromosome 9q34
Which enzyme do allele A and allele B code for, and what is the function?
glycosyltransferase. Takes part in the glycosylation of proteins in the cell membrane.
What does GTA (coded by allele A) and GTB (coded by allele B) transfer to the carbohydrate chain?
GTA: N-acetylgalactose (GalNAc)
GTB: galactose (Gal)
Blood group AB
compound heterozygous for alleles A and B (genotype AB) modify some of their glycoproteins with GalNAc and others with Gal.
What kind of mutation has allele O?
Frameshift deletion
Which blood groups are dominant over blood group O?
A and B.
What kind of disease is OI?
genetically heterogenous disease of the connective tissue.It is a disorder of the calcified as well as soft connective tissues.
What is OI caused by=
deficiency or abnormal production of collagen 1.
On which chromosomes are pro collagen COL1a1 located and COL1A2 located?
COL1A1: chromosome 17
COL1A2: chromosome 7
Mutation, genes, copies that gives rise to mild phenotype of OI type 1. How much reduction of collagen synthesis
Null mutation –> complete loss of one of the 2 copies of either COL1A1 or COL1A2. 50% reduction of collagen synthesis
What kind of mutation leads to OI type 2?
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
Clinical features of OI
- 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)
Mutations in which gene on which chromosome causes Marfan syndrome?
fibrillin-1 (FBN1) gene on chromosome 15q.
What kind of mutations causes Marfan syndrome?
1/4: de novo
70%: missense
Also deletions of FBN1
Symptoms and signs of Marfan syndrome
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.
Progeria syndrome
group of disorders that cause rapid aging in children. monogenic disorders.
Mutation on which gene is responsible for Werner syndrome (progeria adultorum)? Which family does it belong to, and what is it required for?
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.
Symptoms of Werner syndrome
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.
When does children with Hutchinson-Gilford syndrome begin to show symptoms of premature aging, and which gene is affected?
First year of life, LMNA gene.
Which amino acids are found in high content in the polypeptides of OI?
glycine, proline and hydroxyproline. Every third position in the polypeptide sequence is occupied by glycine.
