PEX1mutations in the Zellweger spectrum of the peroxisome biogenesis disorders

Abstract

Diseases of the Zellweger spectrum represent a major subgroup of the peroxisome biogenesis disorders, a group of autosomal-recessive diseases that are characterized by widespread tissue pathology, including neurodegeneration. The Zellweger spectrum represents a clinical continuum, with Zellweger syndrome (ZS) having the most severe phenotype, and neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) having progressively milder phenotypes. Mutations in the PEX1 gene, which encodes a 143-kDa AAA ATPase protein required for peroxisome biogenesis, are the most common cause of the Zellweger spectrum diseases. The PEX1 mutations identified to date comprise insertions, deletions, nonsense, missense, and splice site mutations. Mutations that produce premature truncation codons (PTCs) are distributed throughout the PEX1 gene, whereas the majority of missense mutations segregate with the two essential AAA domains of the PEX1 protein. Severity at the two ends of the Zellweger spectrum correlates broadly with mutation type and impact (i.e., the severe ZS correlates with PTCs on both alleles, and the milder phenotypes correlate with missense mutations), but exceptions to these general correlations exist. This article provides an overview of the currently known PEX1 mutations, and includes, when necessary, revised mutation nomenclature and genotype-phenotype correlations that may be useful for clinical diagnosis.

Antitumorigenic potential of STAT3 alternative splicing modulation

“…4 C and D). Five genes were confirmed to be down-regulated both at the RNA and protein level by the switch to STAT3β, but not by the knockdown: lens epithelium-derived growth factor (LEDGF/ PSIP1, a chromatin-binding protein and transcriptional coactivator; a prosurvival and growth factor) (26); peroxisomal biogenesis factor 1 (PEX1; part of the AAA ATPase subfamily, required for peroxisomal import) (27); CyclinC (CCNC; controls transcription by associating with Cdk8 and modulating RNA pol II activity and regulates both G0/G1 and G2/M transitions) (28); p300/CBP-associated factor (PCAF; histone acetyltransferase and transcriptional coactivator, promotes growth, invasion, and drug resistance) (29); and STAT1β (proliferative antagonist isoform of tumor suppressor STAT1) (30). In the case of STAT1β, the effect is indirect or posttranscriptional, as STAT1α is not affected (Fig.…”

Infantile Refsum Disease: Influence of Dietary Treatment on Plasma Phytanic Acid Levels

“…N, between minimum and maximum reference values detected in the PEX1 gene, as well as by peroxisomal mosaicism, which was observed in the patient's fibroblasts. This child is homozygous for the pathogenic missense variant c.2528G>A (p.Gly843Asp) in PEX1, affecting the second ATP-binding domain of the protein and which may enable transcription into mRNA and translation into protein to a certain extent (Crane et al 2005). As a consequence, the binding between PEX1 and PEX6 is reduced but not abolished.…”

“…while at 37 C import of matrix proteins into "ghost" peroxisomes is observed in some cells (peroxisomal mosaicism), at 30 C, peroxisomal import is almost completely recovered, as well as peroxisomal metabolic functions, and at 40 C, no peroxisomal import is observed (Imamura et al 1998). Overall, this pathogenic variant retains a residual peroxisomal function which, along with peroxisomal mosaicism, results in less severe biochemical deficiencies, a milder clinical phenotype and prolonged survival (Osumi et al 2000;Poll-The et al 2004;Crane et al 2005). This IRD patient was treated with a phytanic acidrestricted diet, since there is increasing evidence on its toxicity, namely, disturbing normal lipid homeostasis (van den Brink and Wanders 2006).…”

“…The missense variant c.2528G>A (p.Gly843Asp) in PEX1 is the most commonly found pathogenic mutation in different patient cohorts (25-40% of the ZSD patients) (Ebberink et al 2011) and is associated with a mild phenotype, meaning that IRD patients may live several decades (Crane et al 2005). Accordingly, an earlier diagnosis will enable a more effective intervention in these patients.…”

“…Presenting neonatally with hypotonia, large fontanels, failure to thrive and cholestatic jaundice, IRD is later recognizable by developmental delay, retinitis pigmentosa, sensorineural deafness, hepatomegaly, growth retardation and milder dysmorphic features (Baumgartner et al 1998;Poll-The et al 2004). The disease progresses slowly and some patients may survive into adulthood, depending on the level of clinical care (Poll-The et al 2004;Crane et al 2005).…”