Genetics Autosomal Dominant and Recessive Disorders pg 56-73
-Many diseases are as a result of a single mutation,
- Single gene/monogenic traits are from 18000 on autosomes, 1000 on X, 57 on Y chromosome.
-Monogenic Traits – are also called mendelian traits, mendel studied 7 traits in a pea plant.
-variation in each of these traits caused by presence of different alleles at single loci.
Principle of Segregation – sexually reproducing organisms possess genes that occur in pairs and only
one pair transmitted to offspring.
Principle of Independent Assortment – genes at different loci are transmitted independently (one pea
plant can be both round and tall, or wrinkled and short.
-states that transmission of one allele does not affect transmission of a different allele.
Genotype – an individual’s genetic constitution at a locus
Phenotype – what is observed physically or clinically
-Genotypes do not always correspond to phenotypes
-Two different genotypes, such as a dominant homozygote and a heterozygote can have the same
phenotype.
An example is Cystic Fibrosis, an autosomal recessive condition which only homozygote is affected
Cystic Fibrosis – one of the most common single-gene disorders in North America, 1:2000 to 1:4000 EU
newborns, less common in other populations
-first identified as “cystic fibrosis” due to fibrotic lesions that develop in the pancreas, one of the
principle organs affected in this disorder
-85% of patients have pancreatic insufficiency (not enough enzymes secreted = malabsorption)
-15-20% of patients have meconium ileus (thickened intestinal matter)
-sweat glands are abnormal, resulting in high levels of chloride in sweat
-sterile due to obstruction of vas deferens
-Major cause of morbidity and mortality in Cystic Fibrosis is pulmonary disease
-intense lower airway inflammation
-chronic bronchial infection (end-stage lung disease)
-airway obstruction due to dehydrated airway surface
-combination of obstruction, inflammation and infection leads to destruction of airways
and death.
-Cystic Fibrosis is caused by mutations in the CFTR gene that encodes the cystic fibrosis transmembrane
conductance regulator (cAMP regulated chloride channel that spans membranes of epithelial cells in
bowel and lung)
-Defect in ion transport results in salt imbalances, depleting the airway of water and producing
obstructive secretions seen in lungs
-explains abnormally high chloride in sweat, because it cannot be reabsorbed
-more than 1500 different mutations at CFTR locus (most common is ∆F508[deletion of F at
508])
-Different mutations predict severity of the disease deltaF508 is a complete lack of chloride
channel production. Other mutations, such as R117H do not produce complete symptoms
Classes of Mutations:
Class 1 – no synthesis of CFTR gene product
Class 2 – defective protein that is destroyed by proteasomes
Class 3 – Produces a protein that gets to cell surface but is abnormally regulated
Class 4 – results in defective chloride ion conductance
Class 5 – promoter or intron-exon splicing mutations that reduce mRNA transcripts,
allowing some normal gene products
Class 6 – Increased turnover of chloride channel at the surface
Same genotype can also produce different phenotypes. An example is phenylketonuria (PKU) which is
seen 1/10000 births.
-mutations in the locus for metabolic enzyme phenylalanine hydroxylase render homozygote
unable to metabolize phenylalanine
-PKU babies are normal at birth but deficiency produces buildup of phenylalanine and its toxic
metabolites
-Highly destructive to CNS, produces mental retardation
-Babies with PKU lose 1-2 IQ points per week during first year of life. Although genotype won’t
change, environmental correction (diet change) can change phenotype.
-Therefore, phenotype is a combination of genetic and environmental factors
(environment can include genes at other loci affecting the gene of interest)
Pedigree – illustrates relationships among family members and shows members affected/unaffected by
disease.
-Proband – an arrow designates first person in whom disease is diagnosed in pedigree
-also sometimes referred to as index case or propositus
-first-degree relatives are related to the parent-offspring or sibline (brother/sister)
-second-degree relatives are those removed by one additional generational step (grandparents,
uncles, aunts, cousins, etc…)
-Autosomal dominant disorders are seen 1:200 people
-Punnett squares can help illustrate matings between simple Genes (Aa, AA, aa)
-Mating between Aa and aa gives 50% chance to pass disease or normal gene to children
-Postaxial polydactyly is the presence of an extra digit next to the fifth digit. (Autosomal dominant)
-no skipping of generations
-if neither parent has disease, none of the children will have disease
Autosomal Dominant Transmissions: characterized by vertical transmission of disease phenotype, a lack
of skipping generations, and equal males and females.
-recurrence risk for autosomal dominant disorders is 50%
-Autosomal recessive diseases are fairly rare, but heterozygous carriers are much more common
-oculocutaneous albinism is autosomal recessive, results from mutation in a gene that encodes
tyrosinase, a tyrosine metabolizing enzyme
-blocks metabolic pathway that normally leads to synthesis of melanin pigment
-can also lead to nystagmus (rapid uncontrolled eye movement)
-strabismus (deviation of eye from normal axis)
-New mutations are a common cause of the appearance of a genetic disease in a person with no
previous family history of the disorder. The recurrence risk for person’s siblings is very low, but
offspring is increased.
Germline Mosaicism – if there is an autosomal dominant or X-linked disease with no family history, can
be due to germline mosaicism, wheremore than one genetically distinct cell line exists in the body.
-mutation occurs in a germline cell during early development, and every cell that arises from
that mutated cell will be phenotypically different
-No somatic cells are affected, so the parent is not affected, but his germline cells will carry the
mutation. Will be transmitted to offspring
-Osteogenesis Imperfecta (Type II) – lethal perinatal form which is caused by mutations in the
type 1 collagen genes.
-unaffected parents with multiple offspring affected led people to believe this was
autosomal recessive, however PCR analysis showed sperm of father had mutation
whereas skin fibroblasts did not
-Other diseases showing germline mosaicism include achondroplasia, neurofibromatosis type I,
Duchenne muscular dystrophy, and hemophelia A
Reduced Penetrance – a person who has a disease-causing genotype might not express the
phenotype, but can transmit the disease to the next generation.
-Retinoblastoma is an example (malignant eye tumor) good example of autosomal
dominant disorder with reduced penetrance
-10% of the obligate carriers (those who have an affected parent and children must
therefore carry the mutation) do not have the disease
-penetrance of genotype is therefore 90%
Retinoblastoma – most common childhood eye tumor (1:20,000 children affected).
-initiates between conception and 4 years old, when retinal cells are proliferatings
-60% of cases are somatic mutations and do not transmit to offspring, 40% are inherited
mutations with ¾ of those being new mutations transmitted by father
-10% of those who have inherited disease genes never form a tumor
-RB1 gene can potentially explain the reduced penetrance seen in retinoblastoma
-RB1 is not the only mutation that needs to happen to cause retinoblastoma, because
otherwise every cell in the body would be at risk for developing a tumor
-The presence of one normal RB1 gene is sufficient to prevent tumor formation
-To initiate tumor formation, a second somatic event must occur to disable the
functional RB1 gene in a retinal cell to produce a tumor.
-Usually multifocal, where a second mutation occurs in multiple locations causing >1 tumors
-Because the second mutations are random, those who inherit the disease allele may never
experience a second hit to initiate tumor formation
-RB1 encodes pRb protein, which binds to E2F transcription factors when hypophosphorylated
and inactivate them.
-Because the cell requires E2F to proceed from G1 to S phase of mitosis, inactivating E2F pRb
stops cell cycle.
-A loss of function pRb mutation will not act to stop the cell cycle, causing aberrant mitosis and
therefore tumor formation
Age-dependent penetrance – a delay in the age of onset of a genetic disease, whereas others
are expressed at birth
-Huntington’s disease is a good example of age-dependent penetrance.
Huntington’s Disease – neurological disorder exhibiting progressive dementia and increasingly
uncontrollable movements of the lumbs
-symptoms are not usually seen until age 30 or later
-affects 1:20000 people of EU descent, less in Africans and Asians.
-progressive loss of motor control, dementia, and psychiatric disorders.
-substantial loss of neurons in the brain, loss of 25% of brainweight, difficulty swallowing,
aspiration pneumonia, cardiorespiratory failure and subdural hematoma
-first genetic disease mapped using an RFLP marker showed mutation is a CAG repeat in exon 1
of the disease causing gene.
-HD gene codes for a protein called huntingtin, which is involved in the transport of vesicles in
secretory pathways, and it is necessary for brain-derived neurotrophic factor
-A person with huntingtons has a 50% chance of inheriting the disease allele
-Other diseases that exhibit age-dependent penetrance are hemochromatosis (iron storage
disorder), familial alzheimers, and many inherited cancers, including autosomal dominant breast
cancer.
Variable Expression – refers to the degree of severity of the disease phenotype
-severity of the disease can vary dramatically, such as in neurofibromatosis type I
-a parent can have a very mild case of neurofibromatosis and transmit it unknowingly to a child,
who can have severe expression.
-Variable expression provides a way for disease alleles to survive at higher frequencies in
populaitons
-Diet, exercise, exposure to harmful agents can affect expression of genetic disease.
-Can result from different types of mutations at the same disease locus – Allelic Heterogeneity
-B-globin mutations can cause either sickle cell or various forms of B-thalassemia
Neurofibromatosis – a disease with highly variable expression
-one of most common autosomal dominant disorders: 1:3000 people
-some patients only have café-au-lait spots (hyperpigmented skin patches), or lisch nodules
(benign growths on the iris) and a few neurofibromas (benign peripheral nerve tumors)
-other patients have severe expression, hundreds to thousands of neurofibromas, optic pathway
gliomas, learning disabilities, hypertension, scoliosis, and malignancies.
-10% of patients present with malignant peripheral nerve sheath tumors
-A mildly affected parent can produce a severe offspring.
-NF1 gene has one of the highest known mutation rates – 50% of patients have new mutations
-large size (350kDa) can account for many mutations
-Gene product, neurofibromin acts as a tumor suppressor
-If NF1 mutation occurs in embryo, it results in somatic mosaicism, where disease expressed in
some parts of the body.
-Neurofibromatosis type II is much rarer and is characterized by vestibular schwannomas
(tumors that arise from schwann cells and affect CN XIII)
-Similarly, CFTR mutations in cystic fibrosis as discussed previously exhibit varying disease
severity depending on how the chloride channels are affected
-complete loss of chloride channels produce heavier symptoms than mutations that
result in partially active chloride channels (allelic heterogeneity)
-Variable expression can be causes by environmental factors, modifier loci, or allelic
heterogeneity.
Locus Heterogeneity – single disease phenotype results from mutations at different loci in
different families
-Adult polycystic kidney disease (APKD) is an autosomal dominant disorder where
accumulation of renal cysts is seen.
-can also develop liver cysts, hypertension, cerebral aneurysms, and cardiovascular
defects
-1:1000 EU patients, 9% of all end-stage renal disease patients
-can be caused by mutations in the PKD1 gene (chr. 16) or PKD2 gene (chr. 4), both of
which code for membrane-spanning glycoproteins and may be involved in cell signaling.
-when gone awry, cell growth is compromised resulting in cysts.
-Can be caused by mutation in either one of these two genes, and be clinically
indistinguishable.
-Osteogenesis imperfect is another disease that can have locus heterogeneity, whereby collagen
alpha1 (chr. 17) and alpha 2(chr. 7) can be mutated and cause osteogenesis imperfecta
-Disease that can be caused by mutations at different loci in different families is said to exhibit locus
heterogeneity.
Pleiotropy – genes that have more than one discernable effect on the body
-Marfan syndrome is an example of an autosomal dominant disorder that affects the eye, the skeleton,
and cardiovascular system.
-Most features caused by unusually stretchy connective tissue
-Caused my mutations in fibrillin, a component of connective tissue that is expressed in most tissues and
organs
Marfan Syndrome – autosomal dominant condition seen in 1:100000 americans. Eye, skeletal, heart
conditions.
-myopia, displaced lense, dolichostenomelia (long slender limbs), pectus excavatum, pectus carinatum,
scoliosis, arachnodactyly (long, slender fingers), joint hypermobility.
-some patients develop prolapse of mitral valve, a condition where cusps of the mitral valve protrude
upward into the left atrium during systole.
-Some patients develop dilatation (widening) of ascending aorta, which can become susceptible to
dissection, can also cause congestive heart failure
-Caused by mutations in fibrillin gene FBN1 that is expressed in aorta, periosteum, and suspensory
ligament of the lens
-FBN1 encodes connective tissue protein called fibrillin, and mutations will alter structure of CT
-Most mutations are missense mutations, but frameshift and nonsense mutations can occur.
Consanguinity in Human Populations – common in many populations within the world
-1st cousin unions are seen in 20-50% of unions in the middle east, resulting in sharing of disease genes
Coefficient of Relationship – quantify percentage of genes shared by a pair of relatives
-siblings share 50% of DNA, uncles and nieces share 25%, first cousins share 1/8 DNA,
etc…
Consanguinity and the Frequency of Recessive Diseases
-1:25 whites is a heterozygous carrier of cystic fibrosis, therefore he has a 1:25 chance of meeting
another carrier if he mates with someone in the general population
-he triples his chance of meeting another carrier if he mates with a first cousin (1/8 chance of
carrying the same gene)
-The rarer the genetic disease, the more likely that parents of an affected individual are consanguineous
since this would dramatically increase the chance of transmitting a disease
-Consanguinity increases the chance that a mating couple will both carry the same disease-causing
mutation. It is seen more often in pedigrees involving rare, recessive diseases than in those involving
common recessive diseases.
-At the population level, consanguinity increases the frequency of genetic disease and mortality. Close
the degree of consanguinity, the greater the increase.