Alpha‐1‐Antitrypsin Deficiency

Suri, Anandini; Patel, Dhiren; Teckman, Jeffery

doi:10.1002/cld.1147

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…To date, there is no specific treatment available to treat specifically hepatic involvement, and liver transplantation is currently the sole option in cases of decompensated cirrhosis [106,107]. Emerging therapies that may prevent the progression of liver disease are currently under investigation [108,109].…”

Section: Assessment Of Liver Diseasementioning

confidence: 99%

Wilson Disease and Alpha1-Antitrypsin Deficiency: A Review of Non-Invasive Diagnostic Tests

Guillaud

Dumortier²,

Couchonnal-Bedoya³

et al. 2023

Diagnostics

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Wilson disease and alpha1-antitrypsin deficiency are two rare genetic diseases that may impact predominantly the liver and/or the brain, and the liver and/or the lung, respectively. The early diagnosis of these diseases is important in order to initiate a specific treatment, when available, ideally before irreversible organ damage, but also to initiate family screening. This review focuses on the non-invasive diagnostic tests available for clinicians in both diseases. These tests are crucial at diagnosis to reduce the potential diagnostic delay and assess organ involvement. They also play a pivotal role during follow-up to monitor disease progression and evaluate treatment efficacy of current or emerging therapies.

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Section: Assessment Of Liver Diseasementioning

confidence: 99%

Wilson Disease and Alpha1-Antitrypsin Deficiency: A Review of Non-Invasive Diagnostic Tests

Guillaud

Dumortier²,

Couchonnal-Bedoya³

et al. 2023

Diagnostics

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“…AAT is synthesized and secreted from hepatocytes for delivery to the lung at grams per day where it binds human neutrophil elastase (NE) and prevents NE-induced degradation of the extracellular matrix (ECM) in the lung 30,31 . Numerous variants in the AAT protein can cause protein misfolding during nascent synthesis in the ER, the first step of the secretory pathway [32][33][34] , leading to aggregation with extended polymers that trigger liver disease phenotypes, such as fibrosis, cirrhosis and hepatocellular carcinoma [35][36][37] . AAT aggregation in the liver results in reduced secretion of functional AAT to the plasma, leading to a loss-of-function in the lung manifested as the inflammatory diseases emphysema, bronchitis and COPD 30,38 .…”

mentioning

confidence: 99%

Tracing genetic diversity captures the molecular basis of misfolding disease

Zhao,

Wang,

Sun

et al. 2024

Nat Commun

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Genetic variation in human populations can result in the misfolding and aggregation of proteins, giving rise to systemic and neurodegenerative diseases that require management by proteostasis. Here, we define the role of GRP94, the endoplasmic reticulum Hsp90 chaperone paralog, in managing alpha-1-antitrypsin deficiency on a residue-by-residue basis using Gaussian process regression-based machine learning to profile the spatial covariance relationships that dictate protein folding arising from sequence variants in the population. Covariance analysis suggests a role for the ATPase activity of GRP94 in controlling the N- to C-terminal cooperative folding of alpha-1-antitrypsin responsible for the correction of liver aggregation and lung-disease phenotypes of alpha-1-antitrypsin deficiency. Gaussian process-based spatial covariance profiling provides a standard model built on covariant principles to evaluate the role of proteostasis components in guiding information flow from genome to proteome in response to genetic variation, potentially allowing us to intervene in the onset and progression of complex multi-system human diseases.

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