Single Gene Disorders I

Question 1

What is an autosomal recessive disorder and its pattern of inheritance?

Answer 1

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

Question 2

What are heterozygous individuals considered in a genetic disorder that is autosomal recessive?

Answer 2

Heterozygous individuals are carriers of the trait and are not affected by the disorder

Characterized by having one remaining functioning allele

Question 3

If both parents are carriers of a autosomal recessive genetic disorder, what percentage of the children will be affected and carriers?

Answer 3

Expect 25% affected children and 50% carrier children

Question 4

What is a key feature of a recessive disorder?

Answer 4

Affected children usually have unaffected parents

Question 5

Where is recessive inheritance often observed?

Answer 5

Often observed with mutations in metabolic enzymes

Question 6

Explain the mode of recessive inheritance. Give an example

Answer 6

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

Question 7

What mode of inheritance are Inborn Errors of Metabolism?

Answer 7

Family of recessive disorders of metabolism like galactosemia, fructose intolerance, and maple syrup urine disease

Question 8

What does consanguinity increase the risk of?

Answer 8

Increases risk of recessive disorders

Question 9

What are the characteristics of a consanguineous union?

Answer 9

Parents share genes from a common ancestor and children have a high degrees of homozygosity in the genome

Question 10

What is the coefficient of consanguinity for children of first cousin unions? What about in uncle-niece unions?

Answer 10

F is 1/16 for children of first cousin unions

F is 1/8 for uncle niece unions

Question 11

Conaguinity effect gets ______ the rarer the mutations are

Answer 11

Stronger

Question 12

What is the definition of autosomal dominant inheritance?

Answer 12

Dominant mutations cause disease in the heterozygous state

One mutant allele is enough to cause disease and the second normal copy cannot compensate

Question 13

In most dominant disorders, the presentation is more severe in the _________

Answer 13

Homozygous state

Question 14

How does dominant inheritance present in the family?

Answer 14

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

Question 15

What is unique to dominant inheritance?

Answer 15

Only type of disorder where 2 affected parents can have a healthy child

If both parents are heterozygous, 25% chance of a healthy child

Question 16

What is haploinsufficiency? What are 2 examples of protein classes?

Answer 16

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

Question 17

When does haploinsufficiency occur?

Answer 17

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)

Question 18

What is the Dominant Negative Effect?

Answer 18

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

Question 19

Where does the Dominant Negative Effect often occur?

Answer 19

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

Question 20

What is an example of the dominant negative effect?

Answer 20

Osteogenesis Imperfecta

A collagen disorder where mutations alter the shape of the collagen subunits

Question 21

What is the Gain of Function Inheritance?

Answer 21

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

Question 22

Where do gain of function mutations usually occur? Give an example.

Answer 22

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

Question 23

What is the “two-hit” model?

Answer 23

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

Question 24

What is an example for the “Two-Hit” Model?

Answer 24

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.

Question 25

What is an X-linked recessive disorder?

Answer 25

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

Question 26

What is an example of X-linked recessive inheritance?

Answer 26

Hemophilia A - factor VIII deficiency (gene is on X chromosome)

Question 27

What is mosaicism? How is it linked to X-linked recessive inheritance?

Answer 27

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.

Question 28

For a daughter who carriers hemophilia and not fully healthy, what will her liver cells be?

Answer 28

Only half of the relevant liver cells produce factor VIII

Heterozygosity for factor VIII mutation causes heavy menstrual bleeds but not hemophilia A

Question 29

What is an example Mosaicism besides Hemophilia A?

Answer 29

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

Question 30

What is X-linked dominant inheritance?

Answer 30

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

Question 31

What are characteristics of mitochondrial disorders?

Answer 31

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

Question 32

What is the inheritance of mitochondrial disorders?

Answer 32

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)

Question 33

What is Codominant Inheritance? What is an example?

Answer 33

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