Memdelian Inheritahce

Question 1

What are the modes of inheritance?

Answer 1

Mendelian:
-Autosomal dominant

• Autosomal recessive
• X-linked recessive
• X-linked dominant
• Y-linked inheritance

Non-Mendelian:
Mitochondrial

Question 2

What are the main autosomal disorders ?

Answer 2

• familial hypercbolesterolemia
• Huntington disease
• myotonic disease
• Marfan syndrome
• osteogenesis imperfecta
• achondroplasia
• neurifibromatosis type I
• Acute intermittent porphyria

Question 3

Explain familial hypercholesterolemia

Answer 3

• The LDL receptor (encoded by LDLR) is localized on the plasma membrane of the hepatocyte
• Low density lipoprotein (LDL) bind to the LDLR to allow endocytosis
• LDL is cleared them from the blood

People who have haploinsufficiency for LDLR have 2x the level of circulating cholesterol

The cholesterol must go somewhere

• heart disease
• Xanthomas May form

Question 4

What is Xanthelasmia?

Answer 4

Cholesterol depositions (xanthoma) that are found near the eye

Xanthomas: yellowish deposition of cholesterol near elbows, ankles, wrists, palpebral areas

Question 5

How is FHC /LDLR deficiency an e ample of allelic heterogeneity?

Answer 5

• Almost an infinite number of different mutation alleles may destroy the function of a gene
• So often these variants may exhibit a high degree of akkeilic heterogeneity

Question 6

What is Huntington disease?

Answer 6

Triplet repeat expansion disorder

• neurodegenerative
• movement disorder

“Gain of function” of the protein

• In this case, “attainment of a novel function”
• This new function leads to death of neurons

Question 7

What are the symptoms of Huntington disease?

Answer 7

• HD symptoms are caused by a degeneration of neurons in the basal ganglia and cortex of the brain
• Symptoms include chorea, cognitive decline, memory loss, sleep disorder

Question 8

What is Myotonic dystrophy?

Answer 8

Caused by a triplet repeat expansion in the DMPK gene

• An example of a triplet repeat expansion disorder that has a pleiotropic phenotype
• Autosomal dominant transmission
• Characterized by wasting of the muscles, cataracts, heart conduction defects, endocrine changes, and myotonia

Question 9

What is pleiotropy?

Answer 9

Many different features (phenotypic manifestations, all ascribed to a single genetic cause

Question 10

Summarize what is myotonia

Answer 10

Reduced ability to relax after a muscle contraction. Don’t confuse myotonia with continuous which is a quick, involuntary jerk

Question 11

What is achondroplasia?

Answer 11

• FGFR3 mutations
  
  • fibroblast growth factor receptor 3
• FGFR3 codes for transmembrane receptor tyrosine kinase that is involved in signaling to control differentiation of cartilage to bone
• Mutations in FGFR3 result in severe stunting of growth

Question 12

How is achondroplasia a gain of function ?

Answer 12

‘Gain of function’ mutation
-Basically, the receptor signals when it is not supposed to

-The FGFR3 gene has a ‘mutation hot spot’ So new mutations are likely to occur de novo in index cases where there is no family history of the disorder

Question 13

Do gain of function exhiniy allelic heterogeneity?

Answer 13

Likely to have little or no alleilic heterogeneity

Question 14

What is Neurofibromatosis?

Answer 14

-Caused by mutations in NF1 gene that codes for neurofibromin protein

• NF1 May be caused by different mutations in the NF1 gene (alleeilic heterogeneity)
  
  • Often, each person (or family) Has a unique mutation

-NF1 gene is very large, there are many places (almost infinite) where a new mutation (de novo) May inactivate the gene

-NF1 gene codes for neurofibromin which is a tumor suppressor protein
-

Question 15

What are the symptoms of Neurofibromatosis (NF1)?

Answer 15

• Cafe-au-spots
• Neurofibromas: usually benign tumors; seen as swellings on the skin
• Lisch nodules in the iris of the eye
• NF1 is a classic example of a disirder that exhibits variable expressivity but has high penetrance

Question 16

What are the symptoms of Marfan syndrome?

Answer 16

-Marfan syndrome: affected individuals have connective tissue problems

• Pleiotropic phenotype is related to connective tissue:
  
  • Chest wall deformity
  • Tall structure, arschnodactyly
  • Risk of heart defect
  • Eye lens subluxation

Question 17

Explain what causes Marfan syndrome

Answer 17

Some forms of Marfan syndrome are explained by dominant negative

-Mutation in the FBN1 gene (fibrillin-1) causes defect in connective tissue

• For dominant negative, both alleles are expressed(autosomal)
  
  • The protein formed from the mutant FBN1 allele doesn’t assemble properly with other proteins
  • Causes higher order protein structures to not form properly in connective tissue (can think of it as an interference)

-Some students find it useful to consider dominant negative to be (sort of) a special case of the gain of function model (this allows it to be considered separately)

Question 18

Only rare examples exist to show autosomal dominance due to haploinsufficiency of an enzyme

Answer 18

-Acute intermittent porphyria as an example (HMBS gene )

• Must have two functional alleles of HMBS because this gene functions in the pathway to synthesize the porphyrin ring and heme
  - A lot of heme is needed in the cell

Most inborn errors of metabolism (due to enzyme deficiency would be recessive- either AR, or X-linked

-This is because an enzyme is a catalyst

• Only a very small amount of enzyme activity is required to meet the needs of the cell
  
  • Example- if approximately 5% of residual PAH activity exists, the baby doesn’t have PKU

Question 19

Explain what is haploinsufficiency

Answer 19

Loss of function mutations in which half normal levels (50%) of the gene product result in phenotypic effects. Reduced protein levels (50%) are not sufficient to carry out the normal of that protein
-Examples include cell some membrane receptors (familial hypercholesterolemia)

• Acute intermittent porphyria (AIP is a rare example of an autosomal dominant enzyme deficiency)(heme can’t be produced fast enough; and pathway intermediates build up and cause disease)
• Osteogenesis imperfecta (OI) type 1 (half the amount of collagen causes brittle bones. OI type I will be discussed in more detail)

Question 20

Why do autosomal dominant mutations manifest in the heterozygous state ?

Answer 20

Haplo-insufficiency

Dominant negative mutations

Question 21

Explain dominant negative mutations

Answer 21

A mutant gene product interferes with the function of the normal gene product; In some cases, the assembly of the multimeric protein is affected (hindered) by the presence of the mutation protein

• Examples include collagenopathies such as severe OI Type II, III or IV; also Marfan syndrome (defect in fibrillin-1)
• Some students prefer to think about dominant negative mutations as a “special case” of gain of function
• Typically, dominant negative mutations produce a more severe phenotype than autosomal dominant by haploinsufficiency
• Both Marfan syndrome, and OI can be caused by either haploinsufficiency, or dominant negative type mutations

Question 22

What are gain of function mutations?

Answer 22

Result from increased levels of gene expression or gene activity or the development of a new function of the gene (as in: “attainment of a novel function”)

Examples:
-Huntington disease (attainment of novel function)

• Achondroplasia (too much of the normal function)
• Many oncogene mutations are thought to be gain of function mutations

Question 23

How does zygosity affect AD disease?

Answer 23

A person who is homozygous for alleles causing an AD disease: the prognosis always worse

LDL receptor defects leading to FH

• Heterozygote (atherosclerosis in adulthood)
• Homozygous (much more severe and childhood onset)

Achondroplasia

• heterozygote has short stature
• homozygous has embryonic, fetal, or perinatal lethality

Huntington disease
-In the few documented examples, homozygous have earlier and more severe disease onset (Early childhood onset)

In all cases, a patient who is homozygous for disease alleles for an AD disorder is extremely rare
-Unless it is clearly indicated, always assume a person with an AD disorder is a heterozygote

Question 24

What are the autosomal recessive e disorders?

Answer 24

• Cystic fibrosis
• Sickle cell anemia
• Phenylketonuria
• Tay-Sachs disease (Hexosaminidase A deficiency )
• Hemochromatosis (delayed age of onset )
• homocystinuria
• Galactosemia
• Alpha 1-antitrypsin deaminase deficiency
• SCID due to adenosine deaminase deficiency
  
  • severe combined immune deficiency
• Most enzyme deficiencies are AR
  
  • Beware those that are X-linked, and AIP (Acute intermittent porphyria which is AD )

Question 25

What is horizontal inheritance?

Answer 25

Autosomal recessive disirders are usually seen in only one generation of a pedigree (horizontal inheritance)

Autosomal recessive disirders are expressed only in the homozygous state. Parents are usually carriers of the disease- causing allele. Siblings are more likely to be affected than others in the population (of course)

-Makes and females are affected in almost equal frequency

Question 26

Explain the relevancy of consanguinity

Answer 26

Finding an autosomal recessive pedigree

• In Western cultures consanguity is usually NOT the cause of an AR disorder in the family
• However, the more rare a disorder is, the more likely consanguity might play a role

Related individuals may carry the same disorders-causing allele

It is not possible to trace the transmission of a mutation through the family without some kind of test (could be biochemical, or genetic) because carriers are typically healthy and problems or phenotypic changes are often difficult to detect

Question 27

Consanguity increases…

Answer 27

The risk that a couple will have a child with a genetic disorder

Question 28

Describe Tay Sachs disease- as an example of an inborn error of metabolism

Answer 28

• Autosomal recessive loss of function of HEXA gene
• Enzyme name is hexosaminidase A
• Lysosomal storage disirder
• Accumulation of a lipid (a ganglioside) in the lysosome
• Baby develops normally until mid first year
• Inexorable decline

Question 29

What is heterozygosity ?

Answer 29

Disirders caused by homozygous loss of function mutations (AR) often are caused by two different alleles in an individual

This is called compound heterozygosity- two parents are carriers if the pathogenic variant of CFTR gene

For this couple, each conception has 25% chance that the baby will have CFTR del F508/CFTR R117H and have CF