Single Gene Disorders Flashcards
What kind of proteins can be affected by mutations?
- -Enzymes
- -Transport and storage proteins
- -Structural proteins
- -Proteins involved in growth, differentiation and development
- -Receptor and signaling proteins
Null mutation
Mutation that completely destroys a protein
Loss-of-function mutation
Mutation reducing protein’s activity
Gain-of-function mutation
Mutation altering protein’s activity or give it a new function (typically seen in signal transduction proteins)
Mendelian modes of inheritance
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
Recessive inheritance
Only present when there are two mutant alleles
Typical proteins mutated in recessive inheritance disorders
Mostly observed in defects of enzymes and proteins involving transport and storage; can compensate for loss of one functional allele
How are defective recessive alleles compensated for?
- Protein working harder
2. More protein made
Carrier of recessive genetic disease
Person with one normal dominant allele and one mutated recessive allele
Compound heterozygote
Person affected by recessive disease with two mutant alleles that are not identical (contain different mutations)
Dominant inheritance
Present when one mutant allele is sufficient to cause disease (occurs in heterozygote state)
Typical proteins mutated in dominant inheritance disorders
Mostly observed in defects of structural proteins, proteins involved in growth/differentiation/development, and receptor/signaling proteins
Causes of dominant inheritance (4)
- Haploinsufficiency
- Dominant negative effect
- Gain-of-function mutation
- Lack of backup (two-hit model)
Haploinsufficiency
One functional allele isn’t enough – requires full gene dosage instead of half (ex. structural proteins that are produced in mass quantities)
Dominant negative effect
Abnormal protein competing with wildtype form (ex. collagen; one wrong protein can disrupt whole structure)
Lack of backup (two-hit model)
Predisposition to certain disorders (typically cancers) due to one mutation being inherited and the other spontaneously mutating
Calculate expected genotype frequencies using Punnett square
Parents’ alleles are used as column and row headers with dominant alleles capitalized and recessive alleles in lowercase; possible allele combinations can be visualized
Dominant: affected (heterozygous) + healthy = 50% chance of heterozygous affected child
Recessive: carrier parents = 25% chance of affected child, 50% chance of carrier child
Sex-determining region of Y
Where the genetic information for male development of embryo is found on Y chromosome
Psuedoautosomal region of Y
Region that is homologous to X chromosome for proper alignment with X-chromosome in meiosis
X-linked inheritance
Comes from a mutation on the X chromosome
Autosomal inheritance
Comes from a mutation on an autosome
Mitochondrial inheritance
Does not follow Mendelian rules of inheritance; inherited from mother; variable expression due to the many copies of mitochondrial DNA
Pedigree
A chart to show whether a parent is a carrier of a disease and analyze familial patterns of a disease; can be used to make accurate estimate of risk for a person to be a carrier of a recessive disease and estimate the likelihood of a couple having an infected child
Consanguineous mating
Mating between cousins (important in risk for recessive disorders)
Lifetime risk for single gene disease
2%
Genetic counseling
Counseling for parents seeking advice about the risk of having a child with a genetic disease; requires knowledge of parents’ genotypes and mode of inheritance of disease; performed by a certified genetic counselor
X-chromosome inactivation
In the first week of development, cells inactivate one X-chromosome so that only the genes of the active X-chromosome are expressed; all progeny of the cells have same X-chromosome inactivated; X-chromosome mosaicism can occur if different X-chromosomes are silenced in different cells
How do you conduct a simple linkage analysis?
A linkage/marker analysis is done by looking at certain set of genetic markers on a chromosome; the two genes present in the person with disease can be used to see which were the carrier genes from parents and if there are any other carriers in the family (look at example in notes)
Recurrence risk
Possibility of next child having specific disease; normally remains the same no matter how many children since conceptions are statistically independent events
Characteristics of autosomal recessive diseases
- Affected children usually have unaffected parents
- Both sexes are affected equally
- Consanguinity increases risk
What are examples of autosomal recessive diseases?
Phenylketonuria and cystic fibrosis
Explain impact of consanguinity on risk for recessive disorders
Most people carry 2-3 recessive mutant alleles on average, and closely related individuals often carry those same recessive mutant alleles, which means that they are at higher risk for recessive genetic disorders; higher coefficient of inbreeding
Coefficient of inbreeding
Describes degree of homozygosity
- -Siblings share 50% of their genes, so a child between them would be homozygous for 25% of genes, making coefficient of inbreeding 25% for siblings
- -Cousins have a coefficient of 1/16, meaning individual is homozygous in 1/16 of genes to other
Inborn errors of metabolism (IEM)
Class of autosomal recessive disorders caused by defects in metabolic enzymes; each disease is rare but cumulative incidence is 1/300 births; many are screened for in newborn screens and can be acute or chronic
Acute IEMs
Start in neonatal period and arise from defective metabolism of small molecules (amino acids, sugars, etc.); non-specific symptoms that often include lethargy, poor feeding, seizures, or characteristic smells
Chronic IEMs
Arise from defects in storage and metabolism of large molecules (glycogen, proteoglycans, etc.)
Phenylketonuria (PKU)
Prevalence: 1/2,900 (relatively rare)
Mode of inheritance: AR, chronic IEM
Pathology: defect on phenylalanine hydroxylase gene on chromosome 12 leading to difficulties in tyrosine metabolism
Symptoms: musty odor, abnormal brain development
Other: Newborn screening done (most prevalent IEM)
Cystic fibrosis (CF)
Prevalence: 1/2000 (common)
Mode of inheritance: AR
Pathology: defect in gene for chloride channel on chromosome 7 (CFTR), often due to deletion of amino acid 508 in first nucleotide binding domain affecting post-translational processing
Symptoms: thick mucus covering lung epithelium and GI tract
Uses sweat chloride test, allele heterogeneity, modifier loci
Treatment: maintaining lung function and aiding digestion
Pancreatic sufficiency of CF
Pancreatic sufficient: patients with enough CFTR for normal digestion
Pancreatic insufficient: patients that require supplementation with pancreatic enzymes
Sweat chloride test
Measurement of the electric conductivity of the skin surface to test for cystic fibrosis (patients with CF have salty sweat with high electric conductivity)
Allele heterogeneity
Harboring different mutations in the same gene, leading to different impact on function of gene product (reason for variation in pancreas function in CF patients)
Modifier genes
Normal variations in activity of other proteins that can have an impact on the severity of other mutations (reason for variation in pancreas function in CF patients; known ones are MSD1, NBD1, NBD2)
Fructose 1,6-bisphosphatase deficiency
Mode of inheritance: AR
Pathology: fasting hypoglycemia
See carbohydrate metabolism for more
Sickle cell anemia
Mode of inheritance: AR
Pathology: hemolysis
See hemoglobinopathy for more
Sucrase-isomaltase deficiency
Mode of inheritance: AR
Pathology: sucrose/glucose polymer intolerane
See carbohydrate metabolism for more
Glycogen storage disorders
Mode of inheritance: AR
Pathology: hypoglycemia, accumulation of glycogen
See carbohydrate metabolism for more
Characteristics of autosomal dominant diseases
- Affected child has at least one affected parent
- Both sexes affected equally
- Can be transmitted from father to son
- Often homozygotes more severely affected than heterozygotes
Penetrance
Percentage of people with disease gene who develop symptoms; can be complete or incomplete
Complete penetrance: if a patient has a certain disease, they will present with symptoms at some point
Incomplete penetrance: patients with genotype for disease may not develop symptoms
Expressivity
Severity of the symptoms; can be low, high, or variable
Variable expressivity: not all patients develop same set of symptoms (complicates risk analysis)
Neurofibromatosis (NF)
Prevalence: 1/3500 (relatively rare)
Mode of inheritance: AD
Pathology: mutated neurofibromin (NF1) gene on chromosome 17
Symptoms: multiple tumors (including iris of eye called Lisch nodules and in CNS), café-au-lait spots, mental retardation
Other: new mutations, variable expressivity
Huntington Disease (HD)
Prevalence: 5/100,000 (very rare)
Mode of inheritance: AD
Pathology: Defect of huntingtin gene on chromosome 4 that causes CAG triplet expansions
Symptoms: neurological disorders (ex. dementia, uncontrolled movement of limbs)
Other: new mutations, triplet expansion, anticipation, gain-of-function
Premutation
With Huntington Disease, a person with more than 40 repeats develops the disease; with 35-40 repeats they will most likely not develop it but the next generation will likely have it (= premutation)
Anticipation
Severity of a disease increasing when transmitted through a pedigree due to escalating number of repeats; observed frequently in triplet expansion mutations such as HD
Delayed age of onset
A disorder that does not manifest itself until later in life (ex. Huntington Disease does not display symptoms until about age 40)
Achondroplasia
Mode of inheritance: AD
Pathology: mutation in fibroblast growth factor receptor gene (FGFR3) on chromosome 4
Symptoms: small stature due to inhibition of bone growth
Other: new mutations, reduced fitness (20% fertility), dominant negative allele, mutation hotspot
Fitness
Chance of reproduction of an affected patient that will pass on the inherited disorder; many disorders reduce fitness by causing infertility or death before reproductive age; when fitness = 0, affected individual cannot reproduce at all
Mutation hotspot
Chromosomal region where mutations occur frequently that normally consists of CG dinucleotide repeat that is methylated (ex. G1138 on FGFR3 gene in achondroplasia)
What disorders often see new mutations? In which genes? Why?
Duchenne Muscular Dystrophy (dystrophin), Neurofibromatosis (NF1), Achondroplasia (FGFR3)
–Genes are large, complex, or have mutation hotspots
Ehlers-Danlos Syndrome (EDS)
Prevalence: 1/10000 for all collagen disorders
Mode of inheritance: AR (mutations in enzymes required for processing) and AD (dominant negative due to misfolded collagen)
Pathology: collagen disorder
Other: genetic heterogeneity
Osteogenesis imperfecta I (OI)
Mode of inheritance: AD
Pathology: defective type I collagen
Dominant negative alleles, allele heterogeneity
Dominant negative effect of OI
2 Proα1 and one Proα2 chain assemble to form procollagen, and this is interrupted by a defective chain that disturbs the larger structure; cause of Type II (perinatal lethal), Type III (progressive deforming), and Type IV (mildest form)
Haploinsufficiency of OI-1
One copy of the gene is not enough to satisfy demand for collagen molecules in tissue; cause of Type I (mild)
Familial Hypercholesterolemia
Prevalence: 1/500 (frequent)
Mode of inheritance: AD
Pathology: defective LDL receptor; LDL levels are doubled in heterozygotes and quadrupled in homozygotes
Other: allele heterogeneity
Dominant inheritance of familial hypercholesterolemia
Any malfunction in the LDL receptor will cause elevated plasma LDL levels due to the fact that it is a transfer/storage protein and is required for the metabolism of cholesterol
Gain-of-function mutations in RET gene
Can render signaling molecule constitutively active, causing Multiple Endocrine Neoplasia (MEN) due to proliferation of neuroendocrine cells; overrides action of wildtype product
Loss-of-function mutations in RET gene
Can destroy the molecule’s ability to respond to stimulus, causing Hirschsprung disease due to impairment of colon neuron development; upsets development because of haploinsufficiency
Barr bodies
Inactivated X-chromosomes that condense at the periphery of the nucleus; only found in females
Characteristics of X-linked recessive disorders
- No father-son transmission
- Affected boys usually have unaffected parents
- Males affected more frequently than girls
- Seems to “skip generations”
Duchenne Muscular Dystrophy (DMD)
Prevalence: 1/3000 (relatively rare)
Mode of inheritance: XR
Pathology: defect in dystrophin
Other: new mutations, large target
Glucose-6-phosphate dehydrogenase deficiency
Mode of inheritance: XR
Pathology: sensitivity to H2O2-generating agents and fava beans
See carbohydrate metabolism for more
Characteristics of X-linked dominant disorders
- No father-son transmission
- All daughters of affected father are affected
- Females more frequently affected
- Typically lethal in males
Leber’s Hereditary Optic Neuropathy (LHON)
Prevalence: 1/50000 (very rare)
Mode of inheritance: mitochondrial
Pathology: defect on mitochondrial DNA in ND1 gene
Symptoms: deterioration of optic nerve, causing blindness early in adulthood
Other: heteroplasmy
Heteroplasmy
Cells contain varying fractions of defective mtDNA molecules in mitochondrial disorders
Mode of inheritance explained by pedigree
Use chart from notes
