Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency.
Hepatology
; 80(4): 859-871, 2024 10 01.
Article
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| MEDLINE
| ID: mdl-38557779
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fenotipo
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Autofagia
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Alfa 1-Antitripsina
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Deficiencia de alfa 1-Antitripsina
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Péptidos y Proteínas de Señalización Intracelular
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Proteínas de la Membrana
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Hepatology
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos