Characterization of the intracellular mechanism causing the alpha-1-antitrypsin Nullgranite falls deficiency state.

Publication Type	Academic Article
Authors	Holmes M, Curiel D, Brantly M, Crystal R
Journal	Am Rev Respir Dis
Volume	140
Issue	6
Pagination	1662-7
Date Published	12/01/1989
ISSN	0003-0805
Keywords	alpha 1-Antitrypsin Deficiency
Abstract	The alpha-1-antitrypsin (alpha 1AT) Null alleles are those for which no alpha 1AT can be detected in the serum attributable to the gene. The intracellular consequences of the various substitution, deletion, and insertion mutations causing the Null state can be categorized into two groups: those associated with detectable alpha 1AT mRNA transcripts and those with no detectable alpha 1AT mRNA transcripts. To classify the intracellular mechanism associated with the Nullgranite falls allele (Tyr160 TAC, C deletion, 5' frameshift----Stop160 TAG), a Nullgranite falls homozygote was evaluated. Genotypic diagnosis of the Nullgranite falls homozygous state was determined using the polymerase chain reaction and Nullgranite falls specific primers. Total cellular RNA extracted from alveolar macrophages of the index case was compared to that from a normal M1 homozygote for the presence of alpha 1AT mRNA transcripts using Northern blot analysis and hybridization to either a 32P-labeled full length alpha 1AT cDNA probe or (as a control) a 32P-labeled gamma-actin cDNA probe. Although the macrophages of both the Nullgranite falls homozygote and the normal showed gamma-actin mRNA transcripts in comparable amounts, Nullgranite falls macrophages contained no detectable alpha 1AT mRNA transcripts whereas the normal had the expected 1.8 kb alpha 1AT mRNA transcripts. Thus, the Nullgranite falls allele can be classified along with Nullbellingham as a Null allele associated with no detectable alpha 1AT mRNA. These observations highlight the marked heterogeneity in the molecular processes causing the Null state, despite an identical phenotype at the clinical level.
DOI	10.1164/ajrccm/140.6.1662
PubMed ID	2481421