A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency

TY - JOUR

T1 - A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency

AU - Miranda, E.

AU - Pérez, J.

AU - Ekeowa, U.I.

AU - Hadzic, N.

AU - Kalsheker, N.

AU - Gooptu, Bibekbrata

AU - Portmann, B.

AU - Belorgey, D.

AU - Hill, M.

AU - Chambers, S.

AU - Teckman, J.

AU - Alexander, G.J.

AU - Marciniak, S.J.

AU - Lomas, D.A.

N1 - MEDLINE® is the source for the MeSH terms of this document.

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Alpha1-antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (Glu342Lys) causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes. This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation-specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by α1-antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; α1-antitrypsin King's) identified in a 6-week-old boy who presented with prolonged jaundice. His334Asp α1-antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticulum and show delayed secretion when compared to the wild-type M α1-antitrypsin. The 2C1 antibody recognizes polymers formed by Z and His334Asp α1-antitrypsin despite the mutations directing their effects on different parts of the protein. This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of α1-antitrypsin. Conclusion: Z and shutter domain mutants of α1-antitrypsin form polymers with a shared epitope and so are likely to have a similar structure.

AB - Alpha1-antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (Glu342Lys) causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes. This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation-specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by α1-antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; α1-antitrypsin King's) identified in a 6-week-old boy who presented with prolonged jaundice. His334Asp α1-antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticulum and show delayed secretion when compared to the wild-type M α1-antitrypsin. The 2C1 antibody recognizes polymers formed by Z and His334Asp α1-antitrypsin despite the mutations directing their effects on different parts of the protein. This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of α1-antitrypsin. Conclusion: Z and shutter domain mutants of α1-antitrypsin form polymers with a shared epitope and so are likely to have a similar structure.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-77956389382&md5=048d14e46f44f6840523ac48b4556971

U2 - 10.1002/hep.23760

DO - 10.1002/hep.23760

M3 - Article

AN - SCOPUS:77956389382

SN - 0270-9139

VL - 52

SP - 1078

EP - 1088

JO - Hepatology

JF - Hepatology

IS - 3

ER -