DLA 13- X-linked Flashcards
Describe X-linked recessive disorders
- Preponderance of males
- Skipping of generations
- NO male to male transmission
- Mothers of affected sons are obligate carriers of the mutant gene, daughters of affected males are obligate carriers
- When mom is a carrier, the risk that her daughter is a carrier is 50%
- When a child is affected, look for the disorder in the maternal relatives (maternal uncle/ grandfather/ cousin)
Why does DMD have a ‘very low reproductive ‘genetic’ fitmess’?
Duchenne muscular dystrophy tends to be lethal before the age of 30 (males die), and they are so severely affected they usually dont have children
What is Becker muscular dystrophy ?
- Mutation is in the same gene (DMD) as in Duchenne muscular dystrophy
- Less severe mutations in DMD lead to Becker Michener dystrophy
- More severe mutations in DMD lead to Duchenne Muscular Dystrophy
What is hemophilia A? How does it have allelic heterogeneity?
-Inherited deficiency of clotting factor VIII resulting in increased tendency to bleed-after minor trauma
- A relatively common severe mutation in the factor VIII gene involve inversions of an intron sequence
- Leads to incorrect splicing
-However, many other types of mutations of the Factor VIII gene result in hemophilia A (allelic heterogeneity)
Explain the X-linked SCID
Due to defect in SCIDX1
Caused by a defect in the y-chain (gamma)of the receptor for several different interlukins (IL2RG)
-Also called the yc-cytosine receptor, since interlukins are cytokines
- If T-cells lack this receptor they can’t mature
- In turn, this results in a deficiency of normal B-cell function
What are the obligate carriers in X-linked carriers?
All daughters of a man affected with an X-linked disorder are heterozygous carriers of the mutation. Jay’s mother is also most likely an obligate carrier of the mutation (other possibilities are a new mutation in the ovum or a germline Mosaicism in the ova of Jay’s mom)
What is asymmetric X-inactivation ?
Manifestations in a female are most commonly due to skewed X-inactivation (assymetric X-inactivation )
-If this asymmetric X-chromosome inactivation occurs, the carrier may have a factor VIII activity level below normal and thus experience bleeding problems
These symptoms are generally mild compared to the bleeding problems of the affected male
Give an example of skewed X-inactivation(skewed lyonization)
Women who are carriers of Duchenne muscular dystrophy alleles often have elevated creatine kinase levels
-But there are reports of muscular weakness in DMD carrier females. Examples of ‘manifesting heterozygotes’
This may be due to skewed X-inactivation (skewed lyonization) in these females
-The number of cells that contain the active X-chromosome with the mutation in DMD are large compared to the cells that contain the active X with the functional DMD gene
Describe red/green color blindness as a sex-linked trait
Males are hemizygous for red/green color blindness. 8% of the male population is red/green color deficient
Homozygous, color blindness (1 in 150) exist but are much rarer than color blindness males
Describe rett syndrome as an X-linked disorder
- Rett syndrome affects females more often than males
- Males with the mutant X-gene, usually die in utero (spontaneous abortion) or soon after birth
- Rett syndrome
Explain the inheritance of Incontinenta pigmenti
X-linked dominant also lethal in males
Incontinenta pigmenti
- Males with the disorder die in utero (male lethal)
- Manifests as rashes & blisters in early life
-later, patches of hyperpigmentation, ‘Marble cake appearance
‘ of skin
- Intellectual and learning disability (in some patients)
- Retinal detachment (in some patients)
Variable expressivity in females: Due to the phenomena of X-inactivation
Describe Incontinenta pigmenti: female mosaics
- Incontinenta pigmenti causes patchy, darker pigmentation where the normal X has been inactivated (mutant X is active)
- Areas of normal pigmentation indicate the areas where the normal X is active
Give some examples of X-linked dominant disorders
- Vitamin D resistant Rickets (hypophosohatemic rickets)
- Rett syndrome (lethal in males)
- Incontinenta pigmenti (lethal in males)
What is Non-penetrance?
When someone has the disease genotype but not the phenotype
What does it mean to be fully penetrant?
If all the people carrying the mutation, express the phenotypic manifestations of the disorder
Describe incomplete penetrance
-Penetrance May be dependent on age, especially in adult onset diseases, in which the proportion of people manifesting the disorder increases over time
Called “age dependence penetrance”
-delayed age of onset
- Huntington disease has a high penetrance but a delayed age of onset ,!!!!!!!
- Familial breast cancer has about 95% penetrance by the age of 80 years
What are the reasons for variable expression?
Three reasons:
- Random chance
- Other genetic factors (modifier loci)or sex influence
- Environmental exposure
Give 2 main examples of variable expression
Hemochromatosis- is an iron overload disorder (autosomal recessive disorder)
- Hemochromatosis is more severe in males
- Premenopausal females will menstruate and lose iron
Xeroderma pigmentosum (autosomal recessive )
- more severe in individuals exposed more frequently to environmental UV radiation
- First child would be expected to be more severely affected than the second child
- Parents might know to keep the second child out of the sun
Describe the penetrance and variable expression in Neurofibromatosis
Neurofibromatosis type 1 is an autosomal dominant disorder
- It has a high penetrance but variable expression, even in the members of the same family
- Some have cafe-au lait spots Neurofibromas on the skin, bone deformities, learning disabilities
- Generally all patients with the mutant NF1 gene expess at least some signs of the disorder (high penetrance)
Describe Marfan syndrome and osteogenesis imperfecta as examples of pleiotropy
Marfan syndrome (autosomal dominant)
- mutation in the fibrillin-1 gene
- skeketal abnormalities (arachnodactyly, long limbs, pectus excavatum)
- Hypermobile joints
- Ocular abnormalities (myopia, lens dislocation )
- Cardiovascular disease (mitral valve prolapse, aortic aneurysm)
Osteogenesis imperfecta (brittle bones, blue sclera) is due to a mutation in gene encoding pro-collagen
What are the features of Marfan syndrome ?
- Iliac artery aneurysm
- Tall,thin
- narrow thorax with outward protrusion of the chest wall
- Lon, thin fingers (arachnodactyly) and toes
Describe osteogenesis imperfecta: defect of collagen as a locus heterogeneity
-Mutations of chromosome 17(COL1A1 gene) or chromosome 7 (COL1A2 gene ) lead to the disease manifestations (phenotype) of osteogenesis imperfecta
What disorders demonstrate locus heterogeneity?
- sensinural hearing impairment
- retinis Pigmentosa
- Charcot Marie tooth disease (AD, AR or X-linked)
- SCID( AR and X-linked)
How can breast cancer susceptibility genes exhibit locus heterogeneity?
Mutations in BRCA1 or BRCA2 (two different genes at different locations) cause increased predisposition to hereditary breast cancer
What is allelic heterogeneity?
Different kinds of mutations of the same gene cause the disease:
Neurofibromatosis-1 is caused due to a mutation in the NF1 gene. 1000s of different mutations have been identified in the NF1 gene
The most common mutation causative of cystic fibrosis is a deletion of Phe at the codon 508 of CFTR
-However, 1000s of other CFTR mutations have been reported (including missense, frameshift, nonsense, promoter etc)
Explain allelic heterogeneity of the NF1 gene
- DNA sequencing of the NF1 gene shows different mutations of the NF1 gene in Robert and Amy(note the differences in sequence)
- The NF1 gene is a mutational hot spot. Most people who have a mutation in NF1 leading to neurofibromatosis have a private, or, familial mutation
- Only rare, does the same mutation occur in different families
- Compare this to sickle cell disease which is defined by the glu6val mutation in the gene encoding beta-globin
Summarize the pathology of cystic fibrosis
Pancreas pathology: the pancreatic duct gets clogged because of viscous muscous. May lead to pancreatic insufficiency, and auto degradation
Lung pathology: mucus in the lung of CF patients is very viscous and is not efficiently cleared from lungs and airways
Leads to recurrent infection, inflammation, and lung tissue damage
