L46-47: Single Gene Disorders I-II

Question 1

What is triplet expansion and what is its effect on phenotype? How does this relate to anticipation?

Answer 1

• Higher the number of trinucleotide repeats of a gene, more severe the disease - Anticipation refers to the correlation between the number of TNRs and the severity increase of disease across generations

Question 1

PKU. Inheritance, defect, frequency

Answer 1

• AR - IEM, Defect in Phe hydroxylase, Phe accumulates and damages the CNS. With many other IEM, screened for at birth - 1/2900

Question 1

Sucrase-Isomaltase Deficiency

Answer 1

• AR - Sucrose/glucose polymer intolerance

Question 1

Do you know how to determine mode of pedigree? Do you know how to draw and interpret a pedigree?

Answer 1

Well, find out

Question 1

Ehlers-Danlos Syndrome

Answer 1

• AR and AD collagen disorder - Dominant forms of EDS are caused by mutations in the collage genes. Misfolded collagen molecules exert a dominant negative effect - Other forms of EDS are caused by mutations in enzymes required or the processing of collage molecules. As typical for enzyme defects, these mutations show a recessive mode of inheritance.

Question 3

What is locus heterogeneity?

Answer 3

• Mutations in different genes cause the same phenotype

Question 4

Explain the dominant inheritance of familial hypercholesterolemia

Answer 4

• FH is frequent 1/500 person disease, AD - Heterozygotes have 2-fold elevation in LDL levels as there are insufficient receptors to clear LDL from serum. Homozygotes have 4-fold evelated in LDL levels. This is an example of haploinsufficiency, allele heterogeneity - Symptoms: xanthomas

Question 5

What is allele heterogeneity?

Answer 5

• Different mutations in the same gene cause different phenotypes. Mutations can be gain of function or loss of function

Question 6

Define dominant negative effect

Answer 6

• Dominant negative effect: If the mutation produces an abnormal protein, the mutant protein may compete with the wildtype form. If the protein in question is part of a large complex, the presence of a few deformed mutant proteins may destabilize the structure. A dominant negative effect affects mostly structural proteins

Question 7

Retinoblastoma

Answer 7

• Autosomal dominant inheritance, expression at cellular level is autosomal recessive - Defects in Rb protein, leads to predisposition and / or development of cancer - Two-hit model

Question 8

What is pleiotropy?

Answer 8

• Mutation causes multiple phenotypes, not all carriers of the same mutation display the same set of phenotypes

Question 8

Describe X chromosome inactivation

Answer 8

• In the first week of embryological development, inactivation of X c/s occurs in a random fashion. As a result, progeny cells arising will be mosaics.

Question 9

Define gain of function.

Answer 9

• Gain of function: Mutated protein may have functions different from its wildtype variant. In this case, the few proteins with novel functions will have an effect no matter how many wildtype versions are present. This mechanism is frequently observed in signal transduction proteins.

Question 10

Explain the impact of consanguinity on the risk for recessive disorders. How to calculate risk

Answer 10

• Consanguinity: relationships between two people who share a common ancestor - Since closely related individuals likely carry same mutant alleles inherited from a common ancestor, consanguinous matings will increase the risk for recessive genetic diseases - First cousins have 1/16 (0.0625%) chance of having an affected child

Question 11

Neurofibromatosis type I. Inheritance, defect, frequency

Answer 11

• AD - Neurological defect in neurofibromin gene. Causes multiple benign tumors (neurofibromas) in skin, benign tumors on iris of eye called Lisch nodules, pigmented skin lesions (café-au-lait spots), tumors of CNS and mental retardation. New mutations, complete penetrance and variable expressivity - 1/3500

Question 12

Describe Duschenne/Becker Muscular Dystrophies

Answer 12

• Both common x-linked recessive diseases - Affects 1/3000 - Defect in dystrophin leads to muscle damage. Gene is large target for new mutations. Large target - Pts are wheel-chair bound by age 12, death occurs before repro age

Question 14

Characteristics of inheritance of mitochondrial disorders

Answer 14

• Does not follow Mendelian Rules - Mitochondria inherited from mother - Cells have many mitochondria with many copies of the chromosome, therefore leading to variable expression (heteroplasmy) - Mitochondrial DNA has mutation rate that is ~10X higher than nuclear DNA

Question 14

Achondroplasia. Inheritance, defect, frequency

Answer 14

• AD - Caused by defect in FGFR3, gain of function mutation where receptor is constitutively active, exhibits dominant negative effect. Most frequent form of dwarfirsm. Initiation of bone growth leads to short stature. New mutations occur frequently in this disease. - Mutation hotspot

Question 15

Discuss concept of reduced fitness and new mutations in context of autosomal dominant disorders

Answer 15

• In some autosomal dominant disease, an allele carriers has a reduced chance of reproduction, ie. reduced fitness - Therefore, reduced fitness of the carriers would lead to disappearance of the mutant alleles in populations - However, allele frequencies stay constant as new mutations appear constantly and compensate for the loss of mutant alleles - Low fitness of carriers means high percentage of new mutations - If parents are not affected by dominant disease, affected children could have inherited a new mutation - New mutations are seen in DMD, NF and achondroplasia. Genes implicated in these disorders are large, complex or contain mutation hotspots.

Question 17

Perform a linkage analysis here to determine who is a carrier of this trait

Answer 17

• Affected individual is II-3 who carries A2,B3,C4 from father and A4,B2,C3 from mother. - II-2 carries A4,B2 and C3 from mother and is therefore a carrier - Carriers = parents and II-2 - Mutant allele lies on chromosomes carrying A2,B3,C4 and A4,B2,C3 - Individual alleles are not sufficient to diagnose/implicate an individual

Question 18

Glycogen storage disorders

Answer 18

• AR - Hypoglycemia, accumulation of glycogen

Question 19

Sickle Cell Anemia

Answer 19

• AR - Hemolysis

Question 21

Characteristics of dominant and recessive inheritance patterns

Answer 21

1.) Recessive inheritance: one normal allele prevents disease, recessive inheritance is mostly observed in defects of enzymes/proteins involved in transport and storage, loss of one functional allele can be compromised 2.) Dominant inheritance: mostly observed in defects of structural proteins, proteins involved in growth, differentiation and development and receptor/signaling proteins

Question 22

Li-Fraumeni

Answer 22

• XR - Defects in p53 causes brain tumors and leukemias - Two-hit model

Question 23

What are modifier genes?

Answer 23

• The individual genetic background modifies the phenotype

Question 24

Contrast the effects of gain-of-function and loss-of-function mutations in the RET gene

Answer 24

• RET gene encodes tyrosine kinase receptor located in the plasma membrane. Both mutations below are autosomal dominant. - Loss of function mutation in RET gene causes Hirschprung disease. Receptor has inability to respond to stimulus. In this disease, there is impaired development of neurons that populate the colon giving rise to aganglionic colon. - Gain of function mutation in RET gene causes Multiple Endocrine Neoplasia (MEN). Receptor renders signaling molecule constitutively active. Proliferation of neuroendocrine cells occur.

Question 26

What is penetrance? What is expressivity?

Answer 26

• Penetrance: percentage of people with disease gene who develop symptoms - Expressivity is the severity of the symptoms

Question 27

Huntingtin Disease. Inheritance, defect, frequency

Answer 27

• AD - Neurodegerative disorder causes by gain of function mutation. Triplet expansion in gene causes protein instability. Neurodegenerative disorder with late age onset, age dependent on number of CAG repeats. Premutation = reduced penetrance = 35-40 repeats. 40+ = fully penetrant. New mutations occur frequently in this disease. - 5/100000

Question 28

Contrast haploinsufficiency and dominant negative effect in the development of osteogenesis imperfecta subtypes

Answer 28

• Osteogenesis imperfecta-1 is caused by mutations in the collagen I genes. - OI-1 causes deformity of skeleton and predisposes bones to breakage. - Frequency = 1/10000, AD - There are 4 different classes of OI depending on the number of proalpha1 and 2 collagen chains and also if the chains are defective or not. Defect in one chain may disturb the larger structure. This is referred to as dominant negative effect. - Allele heterogeneity is also exhibited in this disease in that the severity depends on the AA exchanged. Type I have brittle bones and blue sclerae without bone deformities. Type II is perinatal lethal. Type III is progressively deforming. Type IV has bone deformities with predisposition to bone fractures.

Question 29

LHON

Answer 29

• Most prevalent mitochondrial disorder. Rare at 1/50000 - Caused by mutation by ND1 gene (oxphos) - LHON leads to a rapid deterioration of the optic nerve - Exhibits heteroplasmy as mitochondrial disorder

Question 30

Fructose 1,6 bisphosphatase deficiency

Answer 30

• AR - Fasting hypoglycemia

Question 31

Incontinentia pigmenti.

Answer 31

• X-linked dominant. Result from a defect in NEMO (NFkappaB essential modulator) that results in rash in early infancy, mental retardation, microcephaly and defects in tooth development. - It is lethal in male embryos

Question 33

Draw pedigree symbols for: male, female, unknown, affected, obligate carrier, proband, decease, marriage, consanguinity, monozygotic twins and dizygotic twins

Answer 33

Question 34

CF. Inheritance, defect, frequency

Answer 34

• AR - Defect that impairs trafficking of CFTR chloride channel to cell surface causing pulmonary problems and pancreatic malfunction. CF pts have 2-5 times amount of NaCl in sweat. Severity varies (allele heterogeneity, modifier loci): pancreatic sufficient or insufficient - 1/2000

Question 35

Glucose 6-phosphate dehydrogenase deficiency

Answer 35

• XR - Sensitivity to H2o2 generating agents and fava beans

Question 36

Define haploinsufficiency

Answer 36

• Haploinsufficiency: half of gene dosage might not be sufficient for a cell to carry out its function. Many structural proteins are needed in quantities too large to be supplied by just one allele

Question 37

Causes for dominant inheritance

Answer 37

• Haploinsufficiency - Dominant negative effect - Gain of function mutation - Lack of backup (two-hit model)

Question 38

Characteristics of autosomal and x-linked disorders

Answer 38

1.) Autosomal recessive: - Affected children usually have normal parents - Both sexes equally affected - Consanguinity increases risk 2.) Autosomal dominant: - Affected child has at lease one affected parent - Both sexes are equally affected - Disease can be transmitted from father to son - Often homozygotes are more severely affected than heterozygotes 3.) X-linked recessive: - No father-son transmission - Affected boys usually have unaffected parents - Males affected more frequently than girls - Seems to skip generations by transmission through carrier females 4.) X-linked dominant: - No father-son transmission - All daughters of affected fathers are affected - Females are more frequently affected than males - Often lethal in males

Question 39

Define loss-of-function.

Answer 39

• Loss-of-function: mutation reduces the protein’s activity