Autosomal Recessive Disorders Flashcards
four consequences of having multiple allels at a locus
no phenotypic effect
contribute to normal variation of a specific trait
affect disease susceptibility
directly disturbe protien function and cause a monogenic disease
describe the distribution of a carrier vs. non-carrier trait
can use this to determine the probability that one is a carrier
What are some ways that mutations can alter proteins?
primary peptide structure
peptide folding/coiling
subunit assembly
association with other proteins
protein stability
intracellular transport
targetting/packaging in organelles
active site
regulatory sites
consequences of enzyme deficiency
accumulation of substrate A
deficiency of product B
accumulation of alternate product E
Tay-Sachs disease
macular cherry red spot caused by lysosomal storage of the substrage ganglioside GM2 in neurons
neurologic deterioration in 3-6 months, primarily affects Ashkenazi Jews
caused by deficiency of hexosaminidase A through a mutation of the HEXA gene/alpha subunit
consequences of substrate accumulation
stored in lysosomes or cytoplasm
diffused across cell and tissue compartments
excreted in the urine
GM2 catabolism
the proper way to process GM2 is the removal of GalNAc
hexosaminidase formation and function
hexosaminidase status of Tay-Sachs
A is absent B is present, and cleavage of GM2 is absent
hexosaminidase status of Sandhoff
both A and B are absent, and cleavage of GM2 is absent
AB variant
both hexosaminidase A and B are present, but the activator is missing, so the GM2 still cannot be cleaved
symptoms of mucopolysaccharidosis I
joint contractures, joint stiffness, dystosis multiplex, visceromegaly, coarse faces, corneal clouding
mucopolysaccharidoses
a group of 10 or more disorders which are characterized by defective lysosomal degradation of glycosaminoglycans, and this accumulation is damaging ot tissues
genetic heterogeneity
when similar phenotypes are generated by many different enzymes or different mutations of the same enzyme
locus heterogeneity
when very similar phenotypes are caused by deficiencies in different enzymes
allelic heterogeneity
when dissimilar phenotypes are caused by the same allelic mutations
Describe the work of Fratantonia nd Neufeld that letd to a way for the reliable diagnosis of different mucopolysaccharidosis.
used radiolabeled sulfur in patients and then grew different cell lines together
found that two cells with different enzyme deficiencies could complement each other and rescue the phenotype
Which variants of mucopolysaccharidosis demonstrate allelic heterogeneity?
Type I (Hurler and Scheie) and Type II (Hunter)
Which variants of mucoplysaccharidosis demonstrate locus heterogeneity?
type III (Sanfilippo) and Type IV (Marquio)
four sources of variation in genetically determined traits
locus heterogeneity, alleic heterogeneity, epistasis, environment
I-cell disease
results from deficiency of UDP-N-acetylglucosamine transferase, leading to a lack of the mannose-6-phosphate recognition marker, so enzymes don’t make it to the lysosome
similar phenotypes to Hurler Syndrome
glycogen storage diseases
a group of diseases that result in both deficiency of product and accumulation of substrate
most common is the glucose-6-phosphatase deficiency, so children become hypoglycemic during fasting
urea cycle disorders
results in accumulation of substrate and deficiency of product, but they are not considered storage diseases because the substrates are not stored
disease arise from the accumulation of ammonia
treatment involves reduction of protein intake or the utilizatino of alternate metabolic routes for detoxification (ex. supplementing with arginine for a arginosuccinic acid to arginine block)
propionic acidemia
a deficiency of propionyl-CoA carboxylase results in accumulation of substrate and also accumulation of alternate substrate
the build-up of several acidic molecules may cause acidosis and damage to the CNS
multiple carboxylase deficiency
an example of product deficiency causing disease
a defect in the biotinidase enzyme prevents biotin recycling and apocarboxylases are unable to become holocarboxylases
acumulation of ketones and lactic acid can cuase several growth defects and disease symptoms
supplementation with biotin in the diet is an effective treatment
galactosemia
results from the deficiency of Gal-1-P uridyl transferase
causes disease through substrate accumulation and an abnormal metabolite
conversion of accumulated galactose to galactitol also causes cataracts
