TY  - JOUR
ID  - discovery10106609
N2  - The ?-1-antitrypsin (or alpha-1-antitrypsin, A1AT) Z variant is the primary cause of severe A1AT deficiency and forms polymeric chains that aggregate in the endoplasmic reticulum of hepatocytes. Around 2%-5% of Europeans are heterozygous for the Z and WT M allele, and there is evidence of increased risk of liver disease when compared with MM A1AT individuals. We have shown that Z and M A1AT can copolymerize in cell models, but there has been no direct observation of heteropolymer formation in vivo. To this end, we developed a monoclonal antibody (mAb2H2) that specifically binds to M in preference to Z A1AT, localized its epitope using crystallography to a region perturbed by the Z (Glu342Lys) substitution, and used Fab fragments to label polymers isolated from an MZ heterozygote liver explant. Glu342 is critical to the affinity of mAb2H2, since it also recognized the mild S-deficiency variant (Glu264Val) present in circulating polymers from SZ heterozygotes. Negative-stain electron microscopy of the Fab2H2-labeled liver polymers revealed that M comprises around 6% of the polymer subunits in the MZ liver sample. These data demonstrate that Z A1AT can form heteropolymers with polymerization-inert variants in vivo with implications for liver disease in heterozygous individuals.
KW  - Diagnostics
KW  -  Genetic diseases
KW  -  Genetics
KW  -  Hepatology
KW  -  Structural biology
AV  - public
Y1  - 2020/07/23/
A1  - Laffranchi, M
A1  - Elliston, EL
A1  - Miranda, E
A1  - Perez, J
A1  - Ronzoni, R
A1  - Jagger, AM
A1  - Heyer-Chauhan, N
A1  - Brantly, ML
A1  - Fra, A
A1  - Lomas, DA
A1  - Irving, JA
N1  - JCI Insight is an open access journal in which all content is freely available without charge to the user or their institution. Articles accepted beginning July 1, 2020, are published via the Creative Commons Attribution License (CC BY 4.0). Users of articles published under this license are allowed to read, download, copy, distribute, print, search, and link to the full texts of the articles, and use them for any other lawful purpose, without asking prior permission from the publisher or the author.
UR  - http://dx.doi.org/10.1172/jci.insight.135459
JF  - JCI Insight
TI  - Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin
IS  - 14
SN  - 2379-3708
VL  - 5
ER  -