Robbins Chapter 6
Mutations
- Genome mutations – where there is a loss or gain of an entire chromosme
- Chromosome mutations – rearrangement of genetic material leading to visible
changes in the chromosome.
- Gene Mutations – these include substitutions, point mutations, insertions, and
deletions.
- mutations interfere with protein synthesis on many different levels.
Mendelian Disorders
- you can have dominant, recessive, and codominance.
- single mutant genes can result in pleiotropism where there are many end
effects.
- many different mutations can have the same result as well.
Transmission Pattern of Single-Gene Disorders
-
ex.
Autosomal Dominant Disorders – are shown when they are heterozygous.
- So if there is any passage on one of the parents is going to have the
disease.
- Some patients may have developed the disease by a germ line mutation.
- There is also a question of penetrance with the disorder as well as variable
expressivity.
- There is also further complication in that there may be delayed onset of
symptoms. (huntington)
- most loss of function mutations are NOT autosomal dominant because the
ability to make 50% of the enzyme should compensate.
- 2 major categories of non-enzyme proteins affected in autosomal
disorders.
- complex metabolic pathways that are subject to feedback inhibition. –
ie. membrane receptors such as LDL receptors in familial
hypercholesterolemia.
- key structural proteins such as collagen and cytoskeletal elements of
the red cell membrane - leads to a abnormal phenotype – one thing
goes wrong and the whole thing cannot work. (This is known as a
dominant negative because the abnormal allele disrupts the normal
allele)
gain of function mutations are almost always autosomal dominant
Loss of function mutations affect regulatory proteins acting through a
dominant negative effect.
gain of function mutations endow normal proteins with toxic capabilities.
-
Huntington
neurofibromatosis
myotonic dystrophy
tuberous sclerosis
polycystic kidney disease
familial polyposis coli
hereditary spherocytosis
von willebrand disease
MArfans syndrome
Ehlers – Danlos syndrome
osteogenisis imperfecta
achondroplasia
familial hypercholesterolemia.
acute intermittent porphyria.
-
Autosomal recessive Disorders – single largest category.
- parents may not have the disease but siblings may
- recurrence is 25%
- mutant gene occurs in the same frequency
- expression of the defect is more uniform than in the dominant disorders.
- complete penetrance is common
- new mutations are often not picked up clinically due to heterozygosity.
- in many cases enzyme proteins are effected by a loss of function.
- these include all of the inborn errors of metabolism
ex
- cystic fibrosis
- PKU
- galactosemia
- homocystenuria
- lysosomal storage disorders
- alpha 1 antitrypsin deficiency
- wlison disease
- hemochromatosis
- glycogen storage diseases
- sickle cell anemia
- thalassemias
- congenital adrenal hyperplasia
- Ehlers-Danlos syndrome
- Alkaptonuria
- Neurogenic muscular atrophies
- friedrichs ataxia
- spinal muscular atrophy.
-
X linked Disorders – all sex linked disorders are X linked and the majority are
recessive.
-
it is possible that female carriers will express the disease because of the
inactivation of the X chromosome carrying the normal allele.
ex
- Duchenne’s muscular dystrophy
- hemophilia A and B
- Chronic granulomatous disease
- glucose 6 phosphate dehydrogenase deficiency
- aggamaglobulinemia
- Wiskoot aldrich syndrome
- Diabetes insipidus
- Lesch Nyhan syndrome
- Fragile X syndrome.
Biochemical and Molecular Basis of Single-Gene ( Mendelian ) Disorders
- Enzyme Defects and their consequences - in these types of disorders there is a
production of an enzyme with decreased activity or there is a lack of normal
enzyme. Both cases lead to a metabolic block .
- the result of this block can be an accumulation of substrate, as well as
accumulation of the of the intermediates. Build up of substrate can also
lead to the strengthening of side reactions.
- in glactosemia there is an accumulation of galactose. leading to tissue
damage.
- a deficiency in of phenylalanine hydroxylase leads to the accumulation
of Phe.
- there can also be a decrease in the amount of an essential product
necessary for normal function.
- albinism results from a lack of tyrosinase leading to the lack of the
precursor molecule for melanin.
- lack of feedback inhibition can lead to the overproduction of certain
things such as in lesch nyhan syndrome.
- there can be failure to inactivate a tissue damaging substrate.
- in patients that lack alpha 1 antitrypsin will not be able to inactivate
neutrophil elastase thus are unable to check the destruction of elastin
in the lung.
-
Defects in receptors and Transport Systems – in these types of defects there is
and impairment of the receptor mediated endocytosis or through transport
protein.
- in familial hypercholesterolemia there is an inability to transport the LDL
into the cells due to a lack of LDL receptors which leads to the
overproduction of cholesterol
- in cystic fibrosis, there is a problem transporting Cl – ions due to a lack of
the transporter protein.
-
Alterations in Structure, Function, or quantity of Non enzyme proteins –
defects lead to structural changes in the cell which have functional
consequences.
- hemoglobinopathies such as sickle cell leads to problems.
-
Genetically determined Adverse reactions to drugs – these problems only
occur once they are unmasked by drug interaction or drug injury.
- in patients who are G6PD deficient the administration of the antimalraial
drug primaquine will lead to hemolytic anemia.
Disorders Associated With Defects In structural proteins
- Marfans syndrome - disorder of the connective tissues of the body manifested
particularly in the skeleton, eyes, and the cardiovascular system. It is due to a
defect in the fibrillin gene.
- is a dominant negative trait.
- Ehlers-Danolos syndromes – a group of disorders which result from a defect
in collagen synthesis or structure.
- skin is fragile and prone to trauma
- joints are prone to dislocation
- problems with colon, large arteries, eyes, and diaphragmatic hernias.
- caused by a reduction of lysyl hydroxyalse which cross links the collagen
together.
- type III collagen defecs are associated with problems with blood vessels
and intestines.
- can be defect in conversion of procollagen to collagen.
- can also be due to a defect in copper metabolism.
Disorders Associated with defects in receptor proteins
- familial hypercholestrolemia – is the result of a defect in the receptor for LDL
leading to the inability to take it into the cells.
- defect can be due to defect in transcription, transportation, protein binding
characteristics, problems internalizing the LDL, and problems recycling the
LDL once internalized.
- LDL is the transport mechanism of cholesterol. Most of the LDL goes to the
liver. Normally there is binding to surface receptors, internalization and fusion
with lysozomes, lysosomal processing leading to the release of cholesterol.
- cholesterol will then suppress cholesterol synthesis
- activate the esterification of cholesterol
- suppress the synthesis of LDL receptors.
- very common. leads to the high levels of LDL in the blood leadingto
atherosclerosis and accumulation cholesterol in the soft tissues.
disorders associated with defects in enzymes
-
lysosomal storage diseases- normally breakdown occurs in the lysozomes and
leads to a build up where it is normally degraded.
- Tay-Sachs disease – mutation preventing the degredation of GM2
ganglioside. leadign to mental retardation , blindness, cherry red spot on
the retina dna death by 2 or 3 – Seen as a balooning of neurons with
cytoplasmic vacuoles staining positive fir lipids, whorloed configuration
in the cytoplasmic vacuoles on EM and progressive detruction of enurons
with proliferaiton of microglia.
- Niemann-Pick disease – deficiency in sphingomyelinase. leading to the
accumulation of these in macrophages. – leads to diffuse neuronal
involvement – retinal chery spot, massive accumulation of lipids in the
mononuclear phagocytic system leading to splenomegaly , hepatomegaly,
and enlarged lympho nodes.
- Gaucher Disease – group of diseases which are autosomal recessive with
reduced levels of glucocerebrosidases.
- Type 1 is the most common in adults and is non-neuronopathic, leads
to bone erosions and pathological fractures, Life span is not effected
- Type 2 is the acute neruopathic form. associated with acute
hepatosplenomegaly and CNS involvement. Death occurs at a young
age.
- Mucopolysaccharideoses – MPS are deficient in the enzymes breaking
down the mucopolysaccharides. Cells have clear cytoplasm that contain
PAS positive material.
- Hurler’s syndrome is a autosomal recessive version
- X linked recessive Hunter disease
- all of them have coarse facial features, hepatosplenomegaly, corneal
clouding, lesions of cardiac valves, narrowing of the coronary arteries,
joint stiffness, mental retardation.
- glycogen storage diseases – Autosomal recessive.
- hepatic form. – von Gierke disease – due to a hepatic enzyme
deficiency. Leads to an accumulation of glycogen and hypoglycemia.
- myopathic forms – McArdle Disease – where striated muscle is unable
to perform glycolysis – leads to low skeletal muscle glycogen storage,
muscle weakness, muscle cramps after exercise, failure of exercis e
induced rise in blood lactate.
- Misc form – Pompe disease
- Alkaptonuria – black urine, blue/black pigmentation of the ears, nose, and
cheeks. Arthropathy associated with deposition in articular cartilidge
leading to connective tissue problems.
disorders associated with defects associated with defects in proteins that regulate cell
growth
- neurofybromatosis 1 and 2 – Autosomal Dominant – Multiple neural tumors
– cutaneous pigmentation – Lisch nodules
- key features are skeletal lesions
-
patients are at an increased risk for the development of other tumors and
reduced intelligence.
is due to a loss of a tumor suppressor gene
NF2 deletion can have bilateral acoustic nerve tumors in all cases, gliomas,
cafeaulait spots, absence of Lisch nodules.
Disorder with Multifactorial inheritance - likelihood of developing these illnesses are
determined by how many of the mutant genes are inherited.
Normal Karyotype
Cytogenetic Disorder - are either due to an alteration in the number of chromosomes or
an alteration in the structures of chromosomes.
numerical disorders – monosomy, trisomy, and mosaicims.
monosomy and trisomy are often due to non disjunction of gametes
mosaicism is usually are due to mitotic errors in the zygote.
Strucutral abberations in chromosomes
- deletions
- translocations
- isochormosme – where one arm is lost resulting in two short arms or
two long arms.
- inversions
- ring chromosomes.
cytogenic disorders involving autosomes
- trisomy 21 – aka down’s syndrome. Associated with maternal age. There are
also mosaic versions of this disease. Have flat faces, oblique palpebral fissures
and epicanthic folds, severe mental retardation, congenital heart defects,
increased risk for acute lukemia, abnormal immune response, and premature
alzheimers.
- other trisomies – Edwards trisomy 18, Patau trisomy 13 – all have severe
malformations
- chromosome 22q11 deletion syndrome – congenital heart defects,
abnormalities of palate, facial dysmorphism, developmental delay, variable T
cell deficiency, hypoparathyroidism all of which are also seen in DiGeorges.
cytogenic disorders involving sex chromosomes - inbalances of the sex chromosomes are
better tolerated than the rest of the chromosomes. Milder nature of X chromosome
abnormalities are explained by the Lyon hypothesis. Both X chromosomes are required
for normal gametogenesis and thus are activated in germ cells during gametogenesis.
Also X chromosome inactivation will spare areas needed for normal growth and
development.
- kleinfelter syndrome – most commonly XXY
- leading cause of infertility
- eunichoid body habitus
- minimal or no mental retardation
- failure of secondary sex characterisitics
-
-
-
- gynecomastia
- atrophic testis
- plasma follicle stimualting hormone and elevated estrogen levels.
XYY syndrome
- usually tall but phenotypically normal
- some behavioral difficulties
Turner syndrome
- XO or Xi, there can also be mosaics.
- lymphedema of neck, hands, and feet
- webbign of the neck,
- short stature
- broad chest and widely spaced nipples
- primary amenorrhea
- failure of development fo the breasts
- infantile external genitalia
- strophic and fiborous ovaries
- congenital heart disease paricularly aortic coarctation.
Multi-X females
hermaphroditism and pseudohermaphrodism
Single-Gene Disorders With Non Classic Inheritance
Triplet Repeat mutations –
- Include Huntington, myotonic dystophy, and fragile X
- fragile X syndrome - familial mental retardation and the seevrity of which is
associated with the number of triplet repeats. a person inherits or acquires.
- other diseases with unstable nucleotide repeats
mutations in Mitochondrial Genes –
- leber herditary optic neuropathy – mitochondrial DNA comes mostly from the
mother.
genomic imprinting
- prader willi syndrome and angelman syndrome - maternal imprinting where
a epigenetic event result in the inactivation of the other parent’s allele. There
is a deletion in the paternal chromosome leading to two copies of the defective
maternal gene
gonadal mosaicism
Molecular Diagnosis
Diagnosis of Genetic Disease
direct gene diagnosis
indirect DNA diagnosis: linkage analysis.