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Open Access 01-12-2004 | Hypothesis

Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system viathe diazepam binding inhibitor

Author: Rainer Breitling

Published in: BMC Pediatrics | Issue 1/2004

Abstract

Background

Zellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses.

Hypothesis

We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients.

Testing the hypothesis

Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy.

Implications of the hypothesis

We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/4/5/prepub

Title: Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system viathe diazepam binding inhibitor
Author: Rainer Breitling
Publication date: 01-12-2004
Publisher: BioMed Central
Published in: BMC Pediatrics / Issue 1/2004
Electronic ISSN: 1471-2431
DOI: https://doi.org/10.1186/1471-2431-4-5

At a glance: The STEP trials

Springer Medicine

Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system viathe diazepam binding inhibitor

Abstract

Background

Hypothesis

Testing the hypothesis

Implications of the hypothesis

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Hypothesis

Testing the hypothesis

Implications of the hypothesis

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