Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency

• Published in: Hepatology (Baltimore, Md.) Vol. 80; no. 4; pp. 859 - 871
• Main Authors: Tafaleng, Edgar N., Li, Jie, Wang, Yan, Hidvegi, Tunda, Soto-Gutierrez, Alex, Locke, Adam E., Nicholas, Thomas J., Wang, Yung-Chun, Pak, Stephen, Cho, Michael H., Silverman, Edwin K., Silverman, Gary A., Jin, Sheng Chih, Fox, Ira J., Perlmutter, David H.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.10.2024
• Subjects: Adult; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; alpha 1-Antitrypsin Deficiency - genetics; alpha 1-Antitrypsin Deficiency - pathology; Autophagy - genetics; Female; Humans; Intracellular Signaling Peptides and Proteins - genetics; Liver - metabolism; Liver - pathology; Male; Membrane Proteins - genetics; Original : Liver Pathobiology; Pedigree; Phenotype
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1097/HEP.0000000000000865

Background and Aims: In the classical form of α1-antitrypsin deficiency, a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-group of affected homozygotes but relatively little is known about putative modifiers. Here, we carried out genomic sequencing in a uniquely affected family with an index case of liver failure and 2 homozygous siblings with minimal or no liver disease. Their sequences were compared to sequences in well-characterized cohorts of homozygotes with or without liver disease, and then candidate sequence variants were tested for changes in the kinetics of α1-antitrypsin variant Z degradation in iPS-derived hepatocyte-like cells derived from the affected siblings themselves. Approach and Results: Specific variants in autophagy genes MTMR12 and FAM134A could each accelerate the degradation of α1-antitrypsin variant Z in cells from the index patient, but both MTMR12 and FAM134A variants were needed to slow the degradation of α1-antitrypsin variant Z in cells from a protected sib, indicating that inheritance of both variants is needed to mediate the pathogenic effects of hepatic proteotoxicity at the cellular level. Analysis of homozygote cohorts showed that multiple patient-specific variants in proteostasis genes are likely to explain liver disease susceptibility at the population level. Conclusions: These results validate the concept that genetic variation in autophagy function can determine susceptibility to liver disease in α1-antitrypsin deficiency and provide evidence that polygenic mechanisms and multiple patient-specific variants are likely needed for proteotoxic pathology.