Alpha1-antitrypsin deficiency pattern of inheritance

[madchemist89]

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What is the inheritance pattern of alpha1-antrypsin deficiency? Each source seems to classify it in a different way. Some say it is autosomal recessive, others say autosomal dominant, and some say autosomal codominant. Why is there such disagreement?

 

[projectlogic]

It's definitely codominant since both alleles are expressed.

Need M allele to make protein. Any other variation causes reduction in amount of protein produced.

PiMM = normal amount of protein being expressed
PiSZ = reduced amount of protein being expressed (no M allele) (increased risk for emphysema)
PiZZ = severe deficiency in protein (highest risk for emphysema)

 

[madchemist89]

It's definitely codominant since both alleles are expressed.

Need M allele to make protein. Any other variation causes reduction in amount of protein produced.

PiMM = normal amount of protein being expressed
PiSZ = reduced amount of protein being expressed (no M allele) (increased risk for emphysema)
PiZZ = severe deficiency in protein (highest risk for emphysema)

Thanks for the quick reply.

I just found this:

"Dominance/recessiveness refers to phenotype, not genotype. An example to prove the point is sickle cell anemia. The genotype of sickle cell is caused by a single base pair change in the beta-globin gene: normal=GAG (glu), sickle=GTG (val). There are several phenotypes associated with the sickle genotype: -

anemia (a recessive trait)
blood cell sickling (co-dominant)
altered beta-globin electrophoretic mobility (co-dominant)
resistance to malaria (dominant)"

http://en.wikipedia.org/wiki/Recessive_trait#Autosomal_recessive_gene

My guess is that if the trait being studied is increased risk of emphysema, then it is a codominant trait, but if it is studied in other respects, it must be recessive or dominant.

 

[Myxedema]

From Robbins Basic Pathology, 8E:

AAT is a small (394-amino acid) plasma glycoprotein synthesized predominantly by hepatocytes. The AAT gene, located on human chromosome 14, is very polymorphic, and at least 75 forms have been identified. Most allelic variants produce normal or mildly reduced levels of serum AAT. However, homozygotes for the Z allele (PiZZ genotype) have circulating AAT levels that are only 10% of normal levels. AAT alleles are autosomal codominant, and consequently PiMZ heterozygotes have intermediate plasma levels of AAT. The PiZ polypeptide contains a single amino acid substitution that results in misfolding of the nascent polypeptide in the hepatocyte endoplasmic reticulum. Because the mutant protein cannot be secreted by the hepatocyte, it accumulates in the endoplasmic reticulum and triggers the so-called unfolded protein response, which can lead to induction of apoptosis. Curiously, all persons with the PiZZ genotype accumulate AAT in the liver, but only 8% to 20% develop significant liver damage. This manifestation may be related to a genetic tendency in which susceptible persons are less able to degrade accumulated AAT protein within hepatocytes.

 

[Jamiu22]

From Robbins Basic Pathology, 8E:

So it really depends.... can be either ressive, dominant or codominant, depending on the variant causing the AAT deficiency... but when it's PiZZ - the one we see on UWORLD, then it's autosomal dominant??

 

[Phloston]

Co-dominance.

That's it, and that's what the USMLE wants. It's not debatable.