alpha1-antitrypsin Flashcards
what is Z AAT
an allele that leads to decreased AAT plasma levels
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leads to liver and lung sxs
what is AAT, what is it encoded by
alpha1-antitrypsin
(serine protease inhibitor)
encoded by SERPINA1 gene
what is AATD, what is it caused by
alpha1-antitrypsin deficiency
caused by mutations in SERPINA1 gene
two types of AATD mutations
missense mutations- “deficiency variants” (common)
nonsense mutations- “null variants” (rare)
2 types of AATD deficiency variants, which is more severe
Z, S
Z is more severe
AATD deficiency variant causes what
decreased serum levels of AAT
AATD null variant causes what
nonsense-mediated mRNA decay = no detectable AAT in serum
Z AAT mechanism
Z AAT aggregates & forms polymers
->
resistant to degradation / kept as inclusion bodies in hepatocyte ER
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accumulation in liver & lungs
Z AAT mechanism in liver
accumulation = liver damage bc of toxic GOF in protein
Z AAT mechanism in lungs
accumulation = decreased unpolymerized Z AAT in plasma
->
decreased AAT in plasma
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decreased AAT goes to lungs
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respiratory symptoms bc of LOF of AAT in lungs
how does gene-environment interaction relate to AATD
individuals with ZZ genotype (2 disease-causing alleles) who smoke develop emphysema earlier & decrease lifespan by 10 yrs vs. non-smoking ZZ genotype
what is codominant inheritance
both alleles contribute to the phenotype
AATD pattern of inheritance
codominant
what is MZ genotype for AATD
% of normal AAT plasma levels
1 disease-causing allele (heterozygote)
60% of normal AAT plasma levels
what is ZZ genotype for AATD
% of normal AAT plasma levels
2 disease-causing alleles
10-15% of normal AAT plasma levels
MZ genotype disease risk
increased lung disease risk (especially if smoker)
slightly increased risk of liver disease (bc of formation of Z AAT polymers in hepatocytes)
ZZ genotype disease risk
high severe lung disease risk
high severe liver disease risk (bc of accumulation of Z AAT polymers in hepatocytes)
% prevalence of AATD in individuals with COPD
3.6%
what is AATD commonly misdiagnosed as, what is the avg time from first symptom to diagnosis
asthma
AATD time from 1st symptom to diagnosis = 5.6 - 8.3 years
how underdiagnosed is AATD (%)
only 10% of cases have been diagnosed
how do you diagnose AATD
plasma / serum AAT levels
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genotyping
