Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder

Abstract

The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders and can be caused by mutations in any of 12 different currently identified PEX genes resulting in severe multisystemic disorders. To get insight into the spectrum of PEX gene defects among ZSS disorders and to investigate if additional human PEX genes are required for functional peroxisome biogenesis, we assigned over 600 ZSS fibroblast cell lines to different genetic complementation groups. These fibroblast cell lines were subjected to a complementation assay involving fusion by means of polyethylene glycol or a PEX cDNA transfection assay specifically developed for this purpose. In a majority of the cell lines we subsequently determined the underlying mutations by sequence analysis of the implicated PEX genes. The PEX cDNA transfection assay allows for the rapid identification of PEX genes defective in ZSS patients. The assignment of over 600 fibroblast cell lines to different genetic complementation groups provides the most comprehensive and representative overview of the frequency distribution of the different PEX gene defects. We did not identify any novel genetic complementation group, suggesting that all PEX gene defects resulting in peroxisome deficiency are currently known.

PEX14 is required for microtubule-based peroxisome motility in human cells

“…PEX14-deficient fibroblast cell line PEX14T (synonymous K-01 T) (Neufeld et al, 2009), the PEX1-deficient cell line PBDG-01, kindly provided by Ronald Wanders (AMC, The Netherlands) and the PEX5-deficient cell line PBD005 (Dodt et al, 1995) were SV40-transfected for immortalization resulting in PEX1T and PEX5T, respectively. PEX1T cells harbor the two heterozygous and severe mutations c.1960 1961dupCAGTGTGGA (p.T651_W653dup) and c.1108_1109insA (p.I370NfsX2) (Ebberink et al, 2011). PEX14T cells are homozygous for a nonsense mutation in a putative coiled-coil region of PEX14, c.553C>T (p.Q185X) (Shimozawa et al, 2004).…”

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

“…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.…”

“…A reduced dihydroxyacetone phosphate acyltransferase (DHAP-AT) activity in fibroblasts and amniocytes confirms the postnatal and prenatal diagnosis of ZSD (Wanders et al 1995). Finally, identification of pathogenic mutations in a PEX gene (http://www.dbpex.org) is useful for diagnosis, prognosis, and management of a ZSD, but it also enables carrier testing of at-risk relatives and prenatal or preimplantation diagnosis (Ebberink et al 2011).…”

Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene

“…In silico prediction programmes MutationTaster, SIFT and Polyphen-2 considered that the variant was pathogenic. and rhizomelic chondrodysplasia punctata (OMIM: 215100), which is not necessarily more slowly progressive than Zellweger (Zeharia et al, 2007;Regal et al, 2010;Ebberink et al, 2011). These conditions are characterized by a wide phenotypic pleiotropy, including leukodystrophy, developmental delay, seizures, peripheral neuropathy, SNHL, retinopathy, skeletal and craniofacial abnormalities and other organ damage (liver, heart, kidneys) (Braverman et al, 2013).…”

“…These conditions are characterized by a wide phenotypic pleiotropy, including leukodystrophy, developmental delay, seizures, peripheral neuropathy, SNHL, retinopathy, skeletal and craniofacial abnormalities and other organ damage (liver, heart, kidneys) (Braverman et al, 2013). Clinical manifestations are variable from severe, early-childhood lethal Zellweger syndrome to milder more slowly progressive phenotypes in rhizomelic chondroplasia punctata (Motley et al, 2002;Ebberink et al, 2011). Recently, we defined Heimler syndrome, a rare autosomal recessive disorder characterized by SNHL, enamel hypoplasia of the M A N U S C R I P T…”