Memdelian Inheritahce Flashcards
What are the modes of inheritance?
Mendelian:
-Autosomal dominant
- Autosomal recessive
- X-linked recessive
- X-linked dominant
- Y-linked inheritance
Non-Mendelian:
Mitochondrial
What are the main autosomal disorders ?
- familial hypercbolesterolemia
- Huntington disease
- myotonic disease
- Marfan syndrome
- osteogenesis imperfecta
- achondroplasia
- neurifibromatosis type I
- Acute intermittent porphyria
Explain familial hypercholesterolemia
- 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
What is Xanthelasmia?
Cholesterol depositions (xanthoma) that are found near the eye
Xanthomas: yellowish deposition of cholesterol near elbows, ankles, wrists, palpebral areas
How is FHC /LDLR deficiency an e ample of allelic heterogeneity?
- 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
What is Huntington disease?
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
What are the symptoms of Huntington disease?
- 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
What is Myotonic dystrophy?
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
What is pleiotropy?
Many different features (phenotypic manifestations, all ascribed to a single genetic cause
Summarize what is myotonia
Reduced ability to relax after a muscle contraction. Don’t confuse myotonia with continuous which is a quick, involuntary jerk
What is achondroplasia?
- 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
How is achondroplasia a gain of function ?
‘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
Do gain of function exhiniy allelic heterogeneity?
Likely to have little or no alleilic heterogeneity
What is Neurofibromatosis?
-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
-
What are the symptoms of Neurofibromatosis (NF1)?
- 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
What are the symptoms of Marfan syndrome?
-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
Explain what causes Marfan syndrome
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)
Only rare examples exist to show autosomal dominance due to haploinsufficiency of an enzyme
-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
Explain what is haploinsufficiency
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)
Why do autosomal dominant mutations manifest in the heterozygous state ?
Haplo-insufficiency
Dominant negative mutations
Explain dominant negative mutations
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
What are gain of function mutations?
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
How does zygosity affect AD disease?
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
What are the autosomal recessive e disorders?
- 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 )
What is horizontal inheritance?
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
Explain the relevancy of consanguinity
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
Consanguity increases…
The risk that a couple will have a child with a genetic disorder
Describe Tay Sachs disease- as an example of an inborn error of metabolism
- 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
What is heterozygosity ?
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
