Biochemistry 3 Flashcards
Hurler syndrome is autosomal
recessive
Hurler syndrome gene
a-L-iduronidase
Hurler syndrome is a what disorder?
lysosomal storage disorder
Hereditary hemochromatosis gene
HFE
hereditary hemochromatosis is autosomal
recessive
hereditary hemochromatosis causes an
iron overload
Cystic fibrosis gene
CFTR
CF have over _______ mutations reported
1,000
Sickle cell anemia is autosomal
recessive
sickle cell anemia gene
B-globin
sickle cell anemia causes
anemia
PKU is autosomal
recessive
PKU gene
PAH
PKU causes
high blood phenylalanine, mental retardation
B-thalassemia is autosomal
recessive
B-thalassemia gene
B-globin
B-thalassemia causes
hemoglobinopathy
Tay Sachs is autosomal
recessive
Tay Sachs gene
HexA
Tay Sachs is a what disoder?
lysosomal storage disorder
Glycogen storage diseases is autosomal
recessive
glycogen storage disease has
several genes
glycogen storage causes
abnormal glycogen metabolism
Kartagener syndrome is autosomal
recessive
Kartagener syndrome gene
dyein
Kartagener syndrome causes
chronic respiratory infections
Wilson disease is autosomal
recessive
Wilson disease gene
ATP7B
Wilson disease is a what defect?
copper metabolism
Friedrich ataxia is autosomal?
recessive
Friedrich ataxia gene
frataxin
Friedrich ataxia displays?
anticipation
Although HH (hereditary hemochromatosis) is not sex linked…
males are much more commonly affected. female homozygotes may lose the extra iron during menstruation.
New mutations
Newborn with a dominant genetic disease when there is no history of disease in the family. This could be the result of a novel, dominant acting mutation in the germ cell of one of the parents.
Many cases of autosomal dominant diseases turn out to be
new mutations (Rett syndrome, achondroplasia, NF1)
How to determine a new mutation
in depth family history
Recurrence risk for new mutation in other siblings
low
Occurrence risk for affected child’s offspring
50%
Mosaicism
presence of genetically distinct cell lines in the same person (mix or normal and mutated DNA), an individual consists of >1 distinct population of cells
Somatic/constitutional mosaicism
due to mutation soon after fertilization
Example of somatic/constitutional mosaicism
McCune Albright Syndrome
Germline/gonadal mosaicism
due to mutations only in sperm/egg cells
Example of germline/gonadal mosaicism
osteogenesis imperfecta
When two or more offspring present with an autosomal dominant disease when there is no family history, what should be considered?
germline mosaicism
The recurrence risk in OI (germline) is ________ than in achondroplasia (new mutation)
higher
Delayed age of onset
genetic disease that does not manifest until adulthood
With delayed age of onset, individuals are
unaware of the disease until after they have had children and possibly passed on the gene
-symptoms not seen until 30 years or later
-reduces natural selection against disease gene
-nowadays it is possible to screen individuals for gene prior to their producing offspring
ex: Huntington’s disease, hemochromatosis
Reduced penetrance (incomplete penetrance)
have the mutation, but no symptoms in their life
penetrance
indicates the proportion of individuals carrying a particular genotype that also express the associated phenotype
example of reduced penetrance
retinoblastoma (RB)
RB penetrance
90%, meaning that 90% of the individuals with the mutant genotype will develop the disease and 10% will not. The 10% that do not can still transmit the disease to later generations.
Variable expression
concerns the severity of the disease and is independent of penetrance
example of variable expression
NF1, a parent with mild NF1 (almost undetectable) can transmit the gene to a child who can, subsequently, exhibit a much more severe symptom.
Reduced penetrance vs. variable expression
They do not mean the same thing. NF1 is 100% penetrant with variable expressivity. All people who inherit the diseased gene will have symptoms. It is the severity of symptoms that varies.
Rb is 90% penetrant: 10% of the people with the mutated gene will not have any signs of the disease. The causes of variability of expression for diseases is unknown.
Pleiotropic gene
One that exerts its effects on multiple aspects of physiology and anatomy. Examples are CF, Marfan syndrome, von Gierke disease, diabetes
Allelic heterogeneity
refers to a case where different mutations in the same locus produce the same/similar phenotype
ex: cystic fibrosis, B-thalassemia
Locus heterogeneity
Refers to a case where mutations at different gene loci can produce the same phenotype. Pattern of inheritance may be different in some cases
ex: osteogenesis imperfecti
Osteogenesis imperfecti
Can result from mutations in the col1A1 gene (chromosome 17) or by mutations in the col1A2 gene (chromosome 7). The product of both genes is necessary for the formation of the functional type 1 collagen triple helical protein.
Genomic imprinting
A classic example of genomic imprinting is the deletion of genetic material on the long arm of chromosome 15.
Chromosome 15 - if the deletion is inherited from the father, offspring will develop?
Prader Willi syndrome
Chromosome 15 - if the deletion is inherited from the mother, offspring will develop?
Angelman syndrome
Most common causes of chromosome 15 deletions
Uniparental disomy (two copies of a chromosome from same parent) or deletion during gametogenesis (80% cases) are the most common causes
Genetically identical, but two different diseases
both have a deletion in chromosome 15, either from the mother or father
Prader-Willi
short stature, hypotonia, small hands/feet, obesity, hypogonadism, and mild to moderate intellectual disabilities
Angelman
Severe intellectual disabilities, seizures, ataxic gait, characteristic stance
Imprinting
alters the expression of genes such as paternal and maternal chromosomes contribute different amounts of a gene product.
approximately, ______ different genes in humans are imprinted
70
Gene responsible for Angelman syndrome (UBE3A)
involved in ubiquitin mediated protein degradation, strongly expressed in the brain
several genes are responsible for
Prader-willi syndrome, including SNRPN a small nuclear riboprotein expressed in the brain.
Imprinted means
turned off
Anticipation
a disease that displays an earlier age of onset and/or more severe expression in more recent generations of a pedigree.
Anticipation diseases
Huntington disease, myotonic dystrophy, Friedreich ataxia, and Fragile X syndrome
Myotonic dystrophy
A progressive muscle deterioration disease. Analysis of the gene (DMPK, myotonic dystrophy protein kinase) revealed that the disease is caused by an expansion of a trinucleotide repeat (CTG) in the 3’ untranslated portion of the gene
The number of repeats of the CTG sequence seems to fluctuate, even in unaffected individuals.
- 5-50 repeats = no symptoms
➢ 50-100 repeats = mild symptoms
➢ 100-1,000 repeats = full myotonic dystrophy
The number of repeats often
increases in succeeding generations, explaining the phenomena of anticipation. It is believed that slippage of DNA polymerase during DNA replication is the cause.
Consanguinity
Mating between related individuals.
Because relatives often share disease genes inherited from a common ancestor, consanguineous matings are more likely to
produce offspring affected by autosomal recessive disorders.
The closer the relationship,
the more likely that disease
genes are
shared
In the absence of consanguinity, the chances of
meeting another carrier are
extremely remote.
consanguinity must be suspected when
Very rare recessive diseases are seen in a family.
It has been shown that matings between related individuals produce a high frequency of mortality
Genetic burden
It is estimated that each person carries five recessive genes in heterozygous form that would result in a lethal phenotype if they were present in a homozygous state.
