Alternative titles; symbols
HGNC Approved Gene Symbol: PEX6
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:42,963,865-42,979,181 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Heimler syndrome 2 | 616617 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 4A (Zellweger) | 614862 | Autosomal recessive | 3 | |
| Peroxisome biogenesis disorder 4B | 614863 | Autosomal dominant; Autosomal recessive | 3 |
Peroxisomal targeting signals (PTSs) are discrete amino acid sequences capable of directing proteins to the peroxisome. Most peroxisomal matrix proteins contain PTS1, a C-terminal tripeptide of the sequence ser-lys-leu (SKL) or a conservative variant. In contrast, the N-terminal PTS2 consists of approximately 10 amino acids (arg/lys-leu-X5-gln/his-leu) and has been observed in only 3 peroxisomal proteins. The only documented human PTS2-containing proteins are peroxisomal thiolase (604054) and phytanic acid oxidase (266500). Yahraus et al. (1996) stated that the only known human PTS2-containing protein is thiolase. The most extensively studied of the factors involved in peroxisomal protein import is the PTS1 receptor, encoded by the peroxin-5 gene (PEX5; 600414) and defective in Zellweger syndrome. Human PEX5 was originally identified by homology probing the human EST database with the S. cerevisiae PAS8 protein sequence. The continued application of this approach by Yahraus et al. (1996) led to the cloning and characterization of a novel human gene (called PXAAA1 by them) based on its similarity to PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris. The 980-amino acid protein product belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein. Yahraus et al. (1996) found that substitution of an arginine for the conserved lysine residue in the ATPase domain of the PXAAA1 protein abolished its biologic activity, suggesting that it is an ATPase. Furthermore, they showed that the protein is required for stability of the predominantly cytoplasmic PTS1 receptor. Yahraus et al. (1996) concluded that the PXAAA1 protein plays a direct role in peroxisomal protein import and is required for PTS1 receptor activity.
Distel et al. (1996) listed the peroxisomal assembly factor isolated in the rat by Tsukamoto et al. (1995) as identical to PXAAA1 (or PEX6). Tsukamoto et al. (1995) isolated rat peroxisome assembly factor-2 (PAF2) cDNA by functional complementation of the peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP92, using a transient transfection assay. This cDNA encodes a 978-amino acid protein with 2 putative ATP-binding sites. The investigators stated that PAF2 is a member of a putative ATPase family which includes 2 yeast gene products essential for peroxisome assembly. The stable transformant of ZP92 with the cDNA was morphologically and biochemically restored for peroxisome biogenesis. Fibroblasts derived from patients deficient in peroxisome biogenesis (complementation group C) were also complemented with rat PAF2 cDNA, indicating that PAF2 is a strong candidate for the site of the mutation in one peroxisomal complementation group. The proteins of the ATPase family (AAA proteins) participate in a broad range of cellular processes, as indicated by the designation AAA which comes from 'ATPases associated with diverse cellular activities.'
Fukuda et al. (1996) found that the 2,940-bp open reading frame of the human PAF2 cDNA encodes a 980-amino acid protein that shows 87.1% identity with rat PAF2.
Zhang et al. (1999) determined that the PEX6 gene consists of 17 exons and 16 introns, spanning about 14 kb. The largest exon, exon 1, has at least 952 nucleotides.
To determine the chromosomal localization of PXAAA1, Yahraus et al. (1996) probed a panel of mouse/human hybrid cell lines with the full-length PXAAA1 cDNA. Hybridizing fragments specific for human genomic DNA were detected only in the cell lines containing human chromosome 6. The human cDNA was also used to determine the map position of the mouse ortholog by RFLP analysis of an interspecific backcross DNA panel. The mouse gene mapped to chromosome 17 between markers that show homology of synteny to human 6p22-p11.
By fluorescence in situ hybridization, Fukuda et al. (1996) mapped the human PEX6 gene to 6p21.1.
In an Arabidopsis pex6 mutant with defects in peroxisomal matrix protein import, oil body utilization, peroxisomal metabolism and seedling growth, Gonzalez et al. (2018) found that a pex1 missense mutation (pex1-1), uncovered in a screen for second-site suppressors, can restore the growth defect. Although a major function of PEX6 is involvement in PEX5 retrotranslocation from the peroxisomal membrane (via a PEX1-PEX6 heterohexameric ATPase), Gonzalez et al. (2018) found that the pex1-1 mutant restored seedling growth without restoring PEX5 levels. This supports the hypothesis that PEX6 has additional functions in the peroxisome beyond PEX5 recycling.
Peroxisome Biogenesis Disorder 4A (Zellweger)
Yahraus et al. (1996) observed that expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 of the peroxisomal biogenesis disorders (PBD4A,; 614862). Consistent with this observation, a complementation group 4 patient was found to carry mutations in PXAAA1 (601498.0001 and 601498.0002).
Fukuda et al. (1996) found that human PAF2 restores peroxisome assembly after gene transfer to fibroblasts of group C patients. In 2 patients with what they termed group C Zellweger syndrome (group 4 in the Kennedy-Krieger Institute Classification), the authors demonstrated homozygosity for 2 different mutations in the PAF2 gene. Direct sequencing of the PAF2 gene revealed a homozygous 1-bp insertion at nucleotide 510 in 1 patient (601498.0003) and a splice site mutation in intron 3 resulting in skipping of exon 3 in a second patient (601498.0004).
Zhang et al. (1999) clarified the genomic DNA structure of PEX6 and identified mutations in patients from various ethnic groups. Eleven novel mutations (18 alleles) were identified by direct sequencing of the PEX6 cDNA from 10 patients. There was no common mutation, but an exon skip was identified in 2 unrelated Japanese patients. Most of the mutations led to premature termination or large deletions of the PEX6 protein and resulted in the most severe peroxisome biogenesis disorder phenotype of Zellweger syndrome. A patient with an atypical Zellweger syndrome had a missense mutation that was shown to disrupt the cell's ability to form peroxisomes.
Peroxisome Biogenesis Disorder 4B
Matsumoto et al. (2001) provided several lines of evidence indicating that PEX6, the pathogenic gene for PBD of complementation group 4, is impaired also in complementation group 6 PBD. They found that expression of PEX6 restored peroxisome assembly in fibroblasts from a PBD patient (PBD4B; 614863) who was a compound heterozygote for PEX6 gene alleles.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M331, they identified a homozygous missense mutation in the PEX6 gene (601498.0009) in 5 sibs with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children.
Falkenberg et al. (2017) reported heterozygous mutation in the PEX6 gene resulting in a peroxisome biogenesis disorder ('Zellweger spectrum disorder,' ZSD) due to allelic expression imbalance (AEI) promoting the overrepresentation of a pathogenic allele. In 7 unrelated patients with a ZSD and 1 affected half brother, the authors identified heterozygosity for a missense mutation in the PEX6 gene (R860W; 601498.0015), which was inherited from an unaffected parent in 3 of the families. All affected individuals exhibited AEI, with mutant allele levels 3 to 5 times greater than those of the wildtype allele, whereas the heterozygous parents did not show AEI. Analysis of common variants in PEX6 revealed a polymorphic 4-bp deletion in the 3-prime UTR (rs144286892; 601498.0014) that correlated with AEI of PEX6 when present in heterozygosity but not in homozygosity, being heterozygous and located in cis with the R860W mutation in all 8 affected individuals, but homozygous in the 3 unaffected carrier parents. Functional analysis indicated that the PEX6 R860W mutation has a negative effect on PEX1 (602136)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6.
Heimler Syndrome 2
In affected individuals from 2 unrelated families with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; 616617), Ratbi et al. (2015) identified compound heterozygosity for mutations in the PEX6 gene (601498.0010-601498.0013). The authors noted that in contrast to patients with PBDs at the severe end of the clinical spectrum, these patients showed no identifiable dysmorphic or additional neurologic features. Complementation assays in PEX6-null cells with variants from patients with Heimler syndrome-2 demonstrated that all affected individuals had at least 1 PEX variant with residual activity in peroxisomal biogenesis.
In 2 sibs with HMLR2, born of consanguineous Egyptian parents, Zaki et al. (2016) identified a homozygous missense mutation (G413V; 601498.0016) in the PEX6 gene. The mutation, which was identified by genomewide linkage analysis and whole-exome sequencing, segregated with the disorder in the family.
Distel et al. (1996) provided a unified nomenclature for peroxisome biogenesis. By the use of genetic approaches in a wide variety of experimental organisms, 13 proteins required for peroxisome biogenesis had been identified in the previous 10 years. Three of these had been shown to be defective in lethal peroxisome biogenesis disorders (PBDs). However, the diversity of experimental systems had led to a profusion of names for peroxisome assembly genes and proteins and a great array of numbering systems. Distel et al. (1996) suggested that proteins involved in peroxisome biogenesis should be designated 'peroxins,' with PEX representing the gene acronym. Even though defects in peroxisomal metabolic enzymes or transcription factors may affect peroxisome proliferation and/or morphology, such proteins should not, they recommended, be included in this group. The proteins and genes were to be numbered by date of published characterization, both for known factors and those identified in the future. When necessary, species of origin could be specified by 1-letter abbreviations for genus and species (e.g., hsPEX2). To minimize ambiguities in naming additional proteins identified in the future, Distel et al. (1996) urged authors before publication to contact the ad hoc nomenclature committee.
After demonstrating that a newly isolated gene they called PXAAA1 corrected the defect in complementation group 4 PBD, Yahraus et al. (1996) used a gene-specific primer to synthesize PXAAA1 cDNA from normal and group 4 (CG4; PBD4A, 614862) fibroblasts. Fragments of the open reading frame were then amplified by PCR and subjected to SSCP analysis. PXAAA1 SSCP migration variants were detected in 9 of 13 CG4 patients examined, even though only 40% of the ORF had been examined. Direct sequencing of RT-PCR-generated cDNA fragments revealed that one patient was a compound heterozygote for 2 different deletions: an 8-bp deletion (nucleotides 1962-1969), and a 20-bp deletion (nucleotides 2398-2417) together with insertion of a single T (601498.0002). Direct sequencing of amplified genomic DNA revealed that 1 allele contained a G-to-A transition at the -1 position of a splice acceptor site. This resulted in the use of a cryptic splice acceptor site 8 bp downstream of the normal site, generating the 8-bp deletion observed in the cDNA. The father was heterozygous for this splice site mutation. The mother was found to be heterozygous for the 20-bp deletion/1-bp insertion found in the other allele of the patient. Both mutations in this patient (whose cell line had the designation PBD106) shifted the reading frame of the PXAAA1 mRNA. The product of the first allele lacked the C-terminal 326 amino acids of the protein product and instead contained the 3 amino acids trp-leu-asp (WLD) in their place. The product of the second allele lacked the C-terminal 181 amino acids and instead contained 15 novel amino acids. Previous studies cited by Yahraus et al. (1996) demonstrated that mutations which affect the reading frame of an mRNA commonly result in mRNA instability and decreased steady-state levels of mRNA.
For discussion of the 20-bp deletion (nucleotides 2398-2417) and insertion of a single T in the PEX6 gene that was found in compound heterozygous state in PBD4A (614862) fibroblasts by Yahraus et al. (1996), see 601498.0001.
In a cell line from a patient with typical clinical features of Zellweger syndrome (PBD4A; 614862) and ghost peroxisomes (GM04340 in the Coriell Cell Repositories), Fukuda et al. (1996) identified homozygosity for a 1-bp insertion at nucleotide 511 which introduced a premature termination codon in the PXAAA1 gene. The patient was the product of a father-daughter mating.
In a Japanese girl with Zellweger syndrome, complementation group C (PBD4A; 614862), born of nonconsanguineous parents Fukuda et al. (1996) identified a heterozygous mutation in the consensus 5-prime splice site of intron 3 (IVS3+1G-to-A), which led to skipping of exon 3. The patient at birth was small and had severe asphyxia, profound hypotonia, and clonic convulsions. The patient died of respiratory failure at age 7 months. An insertion introducing frameshift in the transcript from the other allele was also detected.
In 2 unrelated Japanese patients with severe Zellweger syndrome of complementation group C (PBD4A; 614862), Zhang et al. (1999) found homozygosity for a G-to-A transition in the first position of intron 7 of the PEX6 gene. Two abnormal splicing patterns were caused by this mutation: one a skipping of exon 7, and the other a skipping of exons 6 and 7.
In a case of severe Zellweger syndrome (PBD4A; 614862) surviving to the age of 8.5 months, Zhang et al. (1999) found homozygosity for a 1-bp deletion, 1301delC. This deletion resulted in a frameshift at serine codon 434 and the creation of a premature termination at codon 449.
In a patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) belonging to complementation group 6 of the peroxisome biogenesis disorders (PBD4B; 614863), Matsumoto et al. (2001) found compound heterozygosity for mutations in the PEX6 gene. One allele had a deletion of nucleotides 619-882 of PEX6; the other allele had a deletion of nucleotides 2095-2362 and an insertion of 21 nucleotides (601498.0008). This patient had been described by Kelley et al. (1986) as Patient 6.
For discussion of the deletion of nucleotides 2095-2362 along with an insertion of 21 nucleotides in the PEX6 gene that was found in compound heterozygous state in a patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) belonging to complementation group 6 of the peroxisome biogenesis disorders (PBD4B; 614863) by Matsumoto et al. (2001), see 601498.0007.
In family M331 (PBD4B; 614863), Najmabadi et al. (2011) identified a homozygous A-to-G mutation in the PEX6 gene at genomic coordinate chr6:43,044,093 (NCBI36), resulting in a leu534-to-pro (L534P) substitution, in 5 sibs with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children.
In 2 sisters with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; 616617), Ratbi et al. (2015) identified compound heterozygosity for a c.821C-T transition (c.821C-T, NM_000287.3) in the PEX6 gene, resulting in a pro274-to-leu (P274L) substitution, and a c.1930C-T transition, resulting in an arg644-to-trp (R644W; 601498.0011) substitution. Both mutations segregated with disease in the family; the previously unreported R644W mutation was not found in 770 in-house exomes, but was present in 4 of 121,396 alleles in the ExAC Browser (minor allele frequency less than 0.000033). Ratbi et al. (2015) noted that the P274L mutation had been detected by Steinberg et al. (2004) in 2 patients with peroxisome biogenesis disorder (PBD) Zellweger syndrome spectrum (see 614862 and 614863), in compound heterozygosity with a splice site mutation and a frameshift mutation, respectively. No clinical information was reported for the Zellweger syndrome spectrum patients, although it was stated that inclusion criteria for the panel under study were elevated very-long-chain fatty acids (VLCFA) with deficient plasmalogen synthesis, and/or mislocalization of catalase (115500), and/or elevated VLCFA and pipecolate. Analysis of plasma, erythrocytes, and fibroblasts from the sisters with Heimler syndrome-2 by Ratbi et al. (2015) did not show any peroxisomal biochemical aberrations, consistent with their relatively very mild disease; however, immunofluorescence microscopy of Heimler patient fibroblasts revealed a mosaic peroxisomal pattern similar to that previously associated with hypomorphic variants. In complementation assays, transfection of PEX1-null cells with the c.821C-T and c.1930C-T variants rescued peroxisomal biogenesis in approximately 2% and 20% of cells, respectively.
For discussion of the c.1930C-T transition (c.1930C-T, NM_000287.3) in the PEX6 gene, resulting in an arg644-to-trp (R644W) substitution, that was found in compound heterozygous state in 2 sisters with Heimler syndrome-2 (HMLR2; 616617) by Ratbi et al. (2015), see 601498.0010.
In monozygotic twin sisters with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; 616617), originally reported by Ong et al. (2006), Ratbi et al. (2015) identified compound heterozygosity for a c.1802G-A transition (c.1802G-A, NM_000287.3) in exon 8 of the PEX6 gene, resulting in an arg601-to-gln (R601Q) substitution, and a 1-bp deletion (c.1841del; 601498.0013) causing a frameshift resulting in a premature termination codon (Leu614ArgfsTer5). Both mutations segregated with disease in the family, and the previously unreported 1-bp deletion was not found in 770 in-house exomes or in public databases. Ratbi et al. (2015) stated that the R601Q mutation had previously been detected in compound heterozygosity in 7 patients with a Zellweger spectrum disorder (see 614862 and 614863) by Yik et al. (2009) and Ebberink et al. (2010). No clinical information was reported for the 7 patients diagnosed with Zellweger spectrum disorder. Noting that the PEX6 c.1082G-A allele is present in the ExAC database at a frequency of 0.41% in the European population, Ratbi et al. (2015) predicted that future whole-exome sequencing would identify additional mildly affected individuals. In complementation assays, transfection of PEX1-null cells with the c.1802G-A and c.1841del variants rescued peroxisomal biogenesis in more than 30% and in no cells, respectively.
For discussion of the 1-bp deletion (c.1841del, NM_000287.3) in the PEX6 gene, causing a frameshift resulting in a premature termination codon (Leu614ArgfsTer5), that was found in compound heterozygous state in twin sisters with Heimler syndrome-2 (HMLR2; 616617) by Ratbi et al. (2015), see 601498.0012.
Falkenberg et al. (2017) noted that a 4-bp deletion in the 3-prime UTR of the PEX6 gene (c.*442_445delTAAA, NM_000287.3; rs144286892) is a commonly occurring polymorphism, with a minor allele frequency of 35% in the 1000 Genomes Project database. The variant disrupts the more distal of 2 known polyadenylation signals of PEX6, located at c.*440_445, resulting in a PEX6 mRNA with a shorter 3-prime UTR (c.*1_*326, versus c.*1_*462). Falkenberg et al. (2017) performed quantitative analysis of PEX6 mRNA expression in fibroblast cell lines with different PEX6 allele combinations and confirmed that the PEX6 c.*442_445delTAAA allele does not produce the longer PEX6 c.*1_462 mRNA. Nevertheless, the total levels of PEX6 mRNA expressed by the PEX6 c.*442_445delTAAA allele were consistently higher than those expressed by the allele without the deletion. Thus allelic expression imbalance (AEI) of PEX6 occurs in all cell lines heterozygous for c.*442_445delTAAA, but not in cell lines homozygous for the polymorphism. Sanger sequencing of PEX6 cDNAs of 22 different fibroblast cell lines from unrelated controls showed AEI of PEX6 in more than 40% of the cell lines, demonstrating that AEI is a common feature of PEX6.
Peroxisome Biogenesis Disorder 4B
In 7 unrelated patients with a Zellweger spectrum disorder (PBD4B; 614863) and 1 affected half brother, Falkenberg et al. (2017) identified heterozygosity for an R860W mutation in the PEX6 gene (601498.0015) that was inherited from an unaffected parent in 3 of the families. The authors demonstrated that all affected individuals were also heterozygous for the c.*442_445delTAAA polymorphism in the 3-prime UTR of the mutant allele. Affected individuals exhibited AEI, with levels of the mutant allele that were 3 to 5 times higher than the wildtype allele, whereas the unaffected parents were homozygous for the polymorphic variant and did not show AEI.
In 7 unrelated patients with a Zellweger spectrum disorder (PBD4B; 614863) and 1 affected half brother, Falkenberg et al. (2017) identified heterozygosity for a c.2578C-T transition (c.2578C-T, NM_000287.3) in the PEX6 gene, resulting in an arg860-to-trp (R860W) substitution at a highly conserved residue that constitutes the arginine finger 2 in the second region of homology (SRH) of the ATP-binding D2 domain. The mutation occurred de novo in 2 patients, but was shown to have been inherited from an unaffected parent in 3 of the families (parental DNA was unavailable from the remaining 2 families). All affected individuals exhibited allelic expression imbalance (AEI), with levels of the mutant allele 3 to 5 times greater than the wildtype allele, whereas the heterozygous parents did not show AEI. Analysis of common variants in PEX6 revealed an AEI-associated polymorphism (rs144286892; 601498.0014) that was present in heterozygosity on the mutant allele in all 8 affected individuals, but for which the 3 unaffected carrier parents were homozygous. Overexpression of the R860W mutant in control fibroblasts resulted in an accumulation of PEX5 (600414) at the peroxisomal membranes and a concomitant defect of catalase import into peroxisomes. Coexpression of mutant and wildtype PEX6 in various ratios in PEX6-deficient fibroblasts demonstrated a significant negative correlation between restoration of peroxisomal matrix protein import and the ratio of mutant to wildtype PEX6. Falkenberg et al. (2017) concluded that the PEX6 R860W mutation exerts a dominant-negative effect on PEX1 (602136)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6.
In 2 sibs, born to consanguineous Egyptian parents, with Heimler syndrome-2 (HMLR2; 616617), Zaki et al. (2016) identified a homozygous c.1238G-T transversion (c.1238G-T, NM_000287.3) in exon 5 of the PEX6 gene, resulting in a gly413-to-val (G413V) substitution at a conserved residue in the HBD domain. The mutation, which was found by genomewide linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The parents were confirmed to be carriers. Functional studies were not performed.
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