Single Gene Disorders I Flashcards
What is an autosomal recessive disorder and its pattern of inheritance?
Recessive mutations cause disease only in homozygous state (two mutant alleles)
Only individuals who have lost function of both maternal and paternal alleles will be affected
What are heterozygous individuals considered in a genetic disorder that is autosomal recessive?
Heterozygous individuals are carriers of the trait and are not affected by the disorder
Characterized by having one remaining functioning allele
If both parents are carriers of a autosomal recessive genetic disorder, what percentage of the children will be affected and carriers?
Expect 25% affected children and 50% carrier children
What is a key feature of a recessive disorder?
Affected children usually have unaffected parents
Where is recessive inheritance often observed?
Often observed with mutations in metabolic enzymes
Explain the mode of recessive inheritance. Give an example
Seen when the loss of one functional allele can be compensated by regulation
Often observed for defects in highly regulated processes
For example, amount of functional protein in the cell declines by 50% in heterozygous carriers, but upregulation of the intact enzymes prevent substrate buildup
What mode of inheritance are Inborn Errors of Metabolism?
Family of recessive disorders of metabolism like galactosemia, fructose intolerance, and maple syrup urine disease
What does consanguinity increase the risk of?
Increases risk of recessive disorders
What are the characteristics of a consanguineous union?
Parents share genes from a common ancestor and children have a high degrees of homozygosity in the genome
What is the coefficient of consanguinity for children of first cousin unions? What about in uncle-niece unions?
F is 1/16 for children of first cousin unions
F is 1/8 for uncle niece unions
Conaguinity effect gets ______ the rarer the mutations are
Stronger
What is the definition of autosomal dominant inheritance?
Dominant mutations cause disease in the heterozygous state
One mutant allele is enough to cause disease and the second normal copy cannot compensate
In most dominant disorders, the presentation is more severe in the _________
Homozygous state
How does dominant inheritance present in the family?
Affected children normally have at least one affected parent
An individual with a dominant disorder has 50% chance of passing the mutation to the next generation
What is unique to dominant inheritance?
Only type of disorder where 2 affected parents can have a healthy child
If both parents are heterozygous, 25% chance of a healthy child
What is haploinsufficiency? What are 2 examples of protein classes?
Dominant Inheritance I
When one intact allele is not enough to maintain function
Receptors: LDL - Familial Hypercholesterolemia - lose half receptors due to mutations which reduces uptake capacity of cell and increases serum LDL
Paracrine and endocrine messengers: Sonic hedgehog - mutation affects the amount of functional signaling protein will impair cell differentiation
When does haploinsufficiency occur?
Often occurs when amount of protein matters more than the activity (ex. LDL)
OR
When the activity of the protein is not regulated (ex. Sonic hedgehog)
What is the Dominant Negative Effect?
Dominant Inheritance 2
When mutation produces a protein that interferes with normal function
Not every mutations completely destroys the gene - missense mutations create an altered protein that can exert a dominant negative effect
Where does the Dominant Negative Effect often occur?
Often occurs when protein that interferes with normal function is part of a larger structure.
Presence of a fraction of misshapen subunit destabilizes the larger assembly, regardless of the other normal subunits
What is an example of the dominant negative effect?
Osteogenesis Imperfecta
A collagen disorder where mutations alter the shape of the collagen subunits
What is the Gain of Function Inheritance?
Dominant Inheritance 3
When the mutations produces a protein that has a new function
Disease will be caused in heterozygous state
Missence mutations can create a protein with novel function and such protein will affect cell function regardless of presence of normal proteins
Where do gain of function mutations usually occur? Give an example.
Often occurs in signaling receptors and results in activation of signaling cascade without binding of a ligand
Receptors like Fibroblast growth factor FGFR3 can be affected. Mutations permanently activate the receptor and generate an intracellular signal even in absence of signal binding
Presence of normal receptors encoded by the functioning allele does not solve the problem so there is inappropriate activation of FGFR3 which causes achondroplasia - most common form of dwarfism
What is the “two-hit” model?
Dominant Inheritance 4 or Loss of Heterozygosity
Mutations in tumor suppressor genes predispose to cancer
Somatic mutations can disable the second intact copy so affected cells lose heterozygosity
What is an example for the “Two-Hit” Model?
Retinoblastoma (Rb)
Normal individuals rarely develop retinoblastoma and can tolerate mutation of one allele
Heterozygotes for Rb mutation develop retinoblastoma before age 5 - do not have backup so more likely to develop tumor
All cells have one functional Rb copy, cancer cells have none.
What is an X-linked recessive disorder?
Males transmit the X chromosome to daughters and not to their sons. Males transmit the Y to their sons
Trait appears to skip generations. An affected grandfather transmits the disorder through his carrier daughters to his grandsons
Affect predominantly males, homozygous females are rare
What is an example of X-linked recessive inheritance?
Hemophilia A - factor VIII deficiency (gene is on X chromosome)
What is mosaicism? How is it linked to X-linked recessive inheritance?
In female cells, one X chromosome is inactivated during development and inactivation is random so can be either paternal or maternal X.
Inactivation fixed - all progeny of that cell will have same X inactivated
Mosaicism results - females will have paternal x chromosome active and the maternal x. Defective X chromosome will impair the function of half of the cells
X chromosome inactivation is why a carrier female for an X-linked recessive inheritance is not fully healthy.
For a daughter who carriers hemophilia and not fully healthy, what will her liver cells be?
Only half of the relevant liver cells produce factor VIII
Heterozygosity for factor VIII mutation causes heavy menstrual bleeds but not hemophilia A
What is an example Mosaicism besides Hemophilia A?
Duchenne Muscular Dystrophy caused by lack of dystrophin
Affected males have no dystrophin in muscles
Carrier females have mix of cells with and without dystrophin - often do not meet diagnostic criteria for disease but not fully normal
What is X-linked dominant inheritance?
Very rare disorders
Main feature is they cause disease in heterozygous females
Females more often affected
Fathers pass disorders to all daughters, none of the sons
Examples: Fragile X syndrome, hypophosphatemic ricketts, and incontinentia pigmenti
What are characteristics of mitochondrial disorders?
Most mitochondrial proteins are encoded in the nucleus - those follow Mendelian rules and include Succinate Dehydrogenase complex (SDHA)
Characteristic non-Mendelian mode of inheritance is with the thirteen mitochondrial proteins that are encoded on mitochondrial DNA
Mitochondrial genes code for OXPHOS proteins (oxidative phosphorylation) - neuropathies, muscle damage
What is the inheritance of mitochondrial disorders?
Mitochondria are passed exclusively from the mother
Effect that a mitochondrial mutations affects all the children of an effected female but none of the children of an affected male.
Severity of disorder in next generation is unpredictable - there is uneven distribution of mutations during mitosis (heteroplasmy)
What is Codominant Inheritance? What is an example?
Both alleles of a genes each produce a distinguishable trait
Heterozygote expresses both traits
Example if MN glycoprotein on red blood cells - LM allege produce M antigen, LN allele produces N antigen. LMLN heterozygote has both antigens
Codominance does not really apply to genetic diseases, but often in highly polymorphic traits where different alleles produce different functional variants
