Autosomal dominant (less commonly autosomal recessive). Phenotype is triggered by strong emotions or physical activity. Presents as seizures, syncope, sudden cardiac death, prolonged QT interval on EKG.
What causes long qt syndrome?
Mutations in genes coding for membrane spanning ion channel proteins involved in generating cardiac action potential. There are numerous genes which can cause this (heterogeneity: one family has a mutation in one gene and another family has another mutation but both present with the same syndrome).
What is phenotype?
The observable expression of a genotype as a morphological, clinical, biochemical or molecular trait. Results from the interaction of the genome and the environment.
What defines a disease?
Currently: An abnormal phenotype as dictated by patient and family history, physical exam, blood, urine, EKG, X-rays, CT scans, angiograms etc.
Abnormal phenotype OF MEDICAL SIGNIFICANCE!
True or false: Interaction between genotype and environment yields phenotype.
For the single monogenic medelian disorders, does genotype predict phenotype?
What are the causes of varibility in phenotypes for single gene disorders.
1) Allelic heterogeneity (not all mutations in gene X are created equal, different mutations can effect the protein differently) 2) Modifier genes 3) Incomplete penetrance (not everyone with the mutation will get the disease) 4) Environmental factors
What is PKU?
Phenylketonuria. Autosomal recessive. Mutations in phenylalanine hydroxlase. Leads to chronic high levels of phenylalanine which is toxic. Causes MR, epilepsy, psychosis, mousy smell. Treatment is a restricted diet.
True or false: There is no variabilty in phenotype for PKU.
False. The severity of the phenotype correlates inversely with the amount of functional enzyme. There are hundreds of possible mutations in the gene which dictate the degree of availability of functional enzyme.
Compare the variable phenotypes for PKU.
PKU: > 1000 nM, severe phenotype Non-PKU hyperphenylalanemia: 120-1000 nM, lower risk of MR Variant PKU: < 120 nM, mildest form
What is Tetrahydrobiopterin (BH4)?
Cofactor for phenylalanine hydroxylase. Its levels are controlled by enzymes involved in its synthesis and recycling. Mutations in genes coding for these enzymes can worsen (modify) or mimic PKU.
True or false: Phenotype of PKU requires an environmental factor.
True. Requires phenylalanine.
What is cystic fibrosis.
Autosomal recessive. Caused by mutations in the CFTR gene. Its protein product functions principally as a cAMP induced Cl- channel. Range of phenotypes depending on the alleles involved (pancreatic insufficiency, lung disease and male infertility).
What is a compound heterozygote?
An individual having 2 DIFFERENT mutated alleles for the same gene.
Is pancreatic insufficiency a common phenotype of cystic fibrosis?
Yes. Find it in the vast majority of patients with CF. Most disease alleles are associated with this.
What is R117H?
CF disease allele associated with pancreatic sufficiency. These mutations are usually dominant. So compound heterozygotes with this allele usually DO NOT suffer from pancreatic insufficiency although they DO have CF.
Is lung disease a common phenotype of cystic fibrosis?
No. Correlation is poor. There are likely unknown genetic modifiers and/or environmental factors which trigger this phenotype. Individuals who are compound heterozygotes for deltaF508 do have better lung function than homozygotes. And even for some mutations, the severity of lung disease is modified by other mutations WITHIN the CFTR gene.
Is Male infertility a common phenotype of CF?
Yes. Vast majority CF patients experience this. There ARE infrequent mutations that cause congenital bilateral absence of the vas deferens WITHOUT pancreatic or lung problems though.
How can the CF phenotype be modified by a 2nd mutation within the CFTR gene?
Within intron 8 of the CFTR gene is a splice acceptor poly T tract that can be of variable length. The severity of lung disease and male infertility in R117H homozygotes is directly related to the length of this section. If 5T then lung disease and infertility is observed. If 7T or 9T, then no lung disease or infertility is observed.
Give a summary of the relationship between phenotype and genotype in CF.
Different aspects of the phenotype manifest more commonly (infertility > pancreatic insufficiency > lung disease). Aspects of phenotypes depends on the alleles involved (allelic heterogeneity), environmental factors (pathogens), second mutations within the CFTR gene, or modifier genes other than CFTR.
What is sickle cell anemia?
Autosomal recessive. Mutations in the beta-globin chain (Val6Glu). Phenotype: Vascular obstruction due to sickled rbcs --> painful sickle cell crisis. Leads to infarction of bone, spleen, kidney, lungs. Loss of spleen can causes a deficiency in host defenses --> susceptibility to infection. These rbcs also have short half life causing anemia. Sickling is caused by low oxygen levels in the capillaries.
Discuss how other genes can modify the sickle cell phenotype.
Expression of the gamma globin gene (hereditary or induced via hydroxyurea) leads to increased production of fetal hemoglobin (not normally produced at significant levels in adulthood). This fetal hemoglobin can make up for mutated/defective adult hemoglobin and can dampen the severity of the phenotype.
Summary of the relationship between sickle cell anemia's genotype and phenotype.
Since genotype causes phenotype (Val6Glu). But the phenotype is modified/precipitated by environmental factors (such as hypoxia) and its severity can be dampened by expression of other genes like gamma globin.
True or false: All mutations cause disease.
False, some mutations are silent and the allele still functions similarly to the "wild type" allele. So just because you have a mutation does not mean you have the disease.
Why are some mutations silent?
1) redundancy of the genetic code 2) some AA substituions are irrelevant to the function of the protein 3) heterozygosity (silences problems that are autosomal recessive) 4) gene expression is usually not rate limiting (except at low levels < 10%) 5) Redudant pathways that make up for losses in other proteins.
What are the requirements for a genotype to be associated with disease?
1) Protein is central to a specific phenotype 2) Mutations affect active site or critical domain 3) If autosomal dominant, inheritance from one parent is sufficient 4) if recessive, the individual must be a homozygote or compound heterzygote
True or false: Different mutations of the same gene associated with disease can cause varying degrees of the same phenotype.
True (we discussed PKU )
True or false: For some genes associated with disease, different mutations can cause very different phenotypes.
True. Different mutations in beta globin produces different diseases (sickle cell, beta thalassemia)
Can a second mutation within the same gene modify the resulting phenotype?
Yes. We discussed the allelic heterogeneity of the CF the poly T tract and its effect on R117H homozyogotes.
True or false: Other modifier genes do not play any role in determining phenotype.
False. They play an important role. We discussed BH4 and PKU (worsens) and gamma globin and sickle cell (makes it better).sPLA2 and Cox2 (knockout) suppresses FAP phenotype in APC mutatns.
True or false: Environmental factors significantly influence phenotype
True (if you got this wrong I would be concerned). We discussed pathogenic infection in CF (respiratory distress phenotype) and hypoxia in sickle cell (sickle cell crisis), phenyalanine for PKU, physical or emotional distress in long QT syndrome
What is an iatrogenic environmental factor? (define it).
Acquired during medical treament.
What explains the prevalence of deleterious mutations in human populations?
Some of these mutations in single genes may modify the response to disease causing environmental factors. Ex: Various CFTR mutations fight against vibrio cholera. Sickle cell mutation prevents malaria.
What is a phenocopy?
When a disease phenotype generally linked to a single gene mutation is caused by a mutation in a DIFFERENT gene. Ex: Mutations in BH4 can cause PKU (not just mutations in phenylalanine hydroxylase). Hypertrophic cardiomyopathy caused by 27 different genes.
What is hypertrophic cardiomyopathy?
Left ventricular hypertrophy causing outflow obstruction. Linked to 27 different genes (causing problems in myofilament assembly, Z-discs, calcium handling)