Autosomal Dominant Flashcards
week 6
expression
Severity or mildness of phenotype
What is expression influenced by?
environmental factors and allelic variants in other genes
Penetrance
Chance that an individual will actully develop symptoms
Partial = alleles manifest a phenotype in some
Full = 100% chance
What are the 4 types of mutated allele classifications (in terms of functional affect)
Hylomorphic – produces protein with reduced activity
Neuromorphic – produces protein with new activity or product
Antimorphic – antagonizes the activity of normal gene product
Hypermorphic- produces protein with increased activity
Features of autosomal dominant inheritance
Vertical degree pattern
Multiple generations affected
Each person normally has an affected parent
Male and females equally affected
Chances of affected child for:
Hetero disease x hetero disease =
Homo disease x homo health =
Hetero disease x homo healthy =
75%
100%
50%
Expression repeat disorders
Dynamic mutation in which there is an increase in the number of repeats in a tri DNA seq.
Causes improper protein function
How does slipping and miss paring in DNA replication = increase in repeats
- backwards slippage
- repeat expansion = hairpin
- hairpin repeats incorporated
What does Knudsib’s two-hit hypothesis propose about how diseases are inherited?
Familial = inherit a mutation, 2nd develops somatically
Sporadic = 2 somatic mutations
Rationale and testing strategy for pre-symptomatic testing.
Test affected family member for specific mutation
Confirm diagnosis of family member at risk ( if treatment is avalaible)
Offer pre-symptomatic testing or asses risk for recurrence
Why is gene therapy better for recessive traits? How can it be used in AD?
replaces nonfunctioning genes with a correct function
for AD = antisense RNA inhibition of gene expression
explain the use of gene therapy for AD diseases.
- start with antisense siRNA complementary to an mRNA target region
- siRNA foms a complex that recognises target region
- target region is cleaved
- loss of protein synthesis (loss of function)
What is the gene affected in Achondroplasia and Hypochondroplasia and what is the normal function of it?
FGFR3
codes for a tyrosine kinase receptor that signals growth
What is the common cause of the muation in achondroplasia and hypocondroplasia?
De novo during embryogenesis
What is the effect of achondroplasia and hypochondraplasia on cell function?
- gain of function
-inhibition of proliferation and hypertrophy of chondrocytes on growth plate
-decreased echnodnral classification
Reproductive expression of disease for Herero vs homo parents with achondropalsia.
If 2 hetero reproduce:
-2/3 dwarfism
1/3 normal
Homozygosity of mutant = incompatible of life.
clinical features of Achondroplasia
Abnormal bone growth
Short stature
Large head
disproportionate limb trunks
With achondroplasia, why is there is an increased risk of death in infancy?
spinal cord compression/ upper airway obstruction (bone does not grow wide enough)
Affected gene, mutation and impact on cell level for hypochondroplasia
Gene
FGFR3
Mutations
p.ANS540Lys
p.Lys650Met
Gain of function –> decreased endochondral ossification, inhibited chondrocyte proliferation in growth plate and decerased cartlidge matrix production
LESS SEVERE
Clinical features of hypochodroplasia
Normal birth and weigth
Disproportionate limb trunk length
Presents as toddlers
Short stature disproportionate to limbs as age
Achondroplasia vs hypochondrial clinical presentations.
Hypo= NO trident hands or facail features
Hypo = normal motor milestones
Affected gene, mutation and effect on phenotype for Huntingtion’s disease.
Gene
-HTT gene
Mutation
-CAG repeat in HTT protein
Phenotype
-HTT protein aggregation on cells = atrophy
Huntington’s disease clinical features
Progressive motor disability
Chorea (jerky involuntary movements)
Cognitive decline
Mental disturbance
Changes in personality
onset depends on number of repeats
Adult onset = 40-55 repeats
Juvenile onset = greater than 60 repeats
Penetrance of Huntington’s
need more than 40 repeats for be 100%
How many repeats of CAG in a person with vs without Huntington’s disease?
Normal person = 10-26
Affected= 36-121
Anticipation
phenomenon in which there is increase disease severity and/ or earlier age of onset in successive generations
Treatment of HD.
None
Potential for gene therapy
What are the three phenotypes of mytonic dystrophy and what determines their expression?
3 phenotypic affects
-mild
-classic
-congineital
Changes from M-C depending on increasing CTG repeats, decreased age of onset and decreased life Expectancy
Affected gene, mutation and penetrance of Myotonic dystrophy
Gene
-DMPK
Mutation
-more than 37 CTG repeats
Penetrance
-need more than 50 for 100%
What organs are affected by myotonic dystrophy?
Skeletal
Eyes
Endocrine
CNS
Mangement of Myotonic dystrophy
assistive devices (wheelchairs etc)
-symptomatic treatment:
-hypothyroidism, pain management arrythmia etc
Genetic deficit and mutated function i retinoblastoma.
Deficit
Loss of function in tumor suppressor gene / RB1
Mutated function
-loss of inhibiting function = uncontrolled cell cycle progression
Main clinical feature of Retinoblastoma
Leukocria (white pupils, clearer in photos).
Inheritance patterns of Retinoblastoma
Inheritance patterns:
Familial or sporadic
Due to loss of function on alleles on RB gene
Life expectancy and inheritance pattern of neurofibromatosis
Inheritance pattern
Knudosons 2-hit hypothesis
Lifespan
-NF1= 8 years lower
-NF2- normal
Gene locus, Clinical features and treament for NG1
Gene locus NF1
17q12
clinical features
Changes in pigmentation
Growth of tumors along nerves in skin/brain
treatment
Surgical removal of disfiguring cutaneous or sub cutaneous neurofibrils
Gene locus, Clinical features and treament for NG2
gene locus
22qq12.2
clinical features
Growth of noncancerous tumours in nervous system = hearing loss and deafness
Vestibular growth schwannomas
treatment
Surgical removal of vesicular schwannomas
Awareness of problems with balance and underwater disorientation
What are the affected genes of PKD and what is the percentage contribution from each of them?
PKD1 = 85%
PKD2 = 15%
Clinical manifestations of Polyccystic Kidney Disease.
The most common clinical presentations are hypertension, anemia, liver cysts, hematuria, flank pain, abdominal masses, urinary tract infections, renal failure, nephrolithiasis, and renal cancer
genetic diversity
The difference in the way that signs and symptoms of a genetic condition can show up in individual patients who have that condition
