| +170995 | ||||||||||||||||||
| ATP-BINDING CASSETTE, SUBFAMILY D, MEMBER 3; ABCD3 | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| PEROXISOMAL MEMBRANE PROTEIN 1; PXMP1 PEROXISOMAL MEMBRANE PROTEIN, 70-KD; PMP70 | ||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||
| ZELLWEGER SYNDROME 2, INCLUDED; ZWS2, INCLUDED | ||||||||||||||||||
| HGNC Approved Gene Symbol: ABCD3 | ||||||||||||||||||
| Cytogenetic location: 1p21.3 Genomic coordinates (GRCh37): 1:94,883,932 - 94,984,218 (from NCBI) | ||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||
| TEXT | ||||||||||||||||||
| Peroxisomes are single, membrane-bound, spheroid organelles present in virtually all eukaryotic cells. The polypeptide composition of the peroxisomal membrane is distinct from that of other organelles and comprises 2 quantitatively major (22K and 70K) and several minor peroxisomal membrane proteins. The peroxisome matrix contains more than 40 enzymes which are involved in a variety of metabolic processes including peroxide-based respiration, synthesis of plasmalogen and bile acids, beta-oxidation of very long chain fatty acids, and glyoxylate transamination. Biogenesis of peroxisomes appears to proceed by import of newly synthesized proteins into existing peroxisomes which enlarge and divide. Most matrix enzymes use an SKL (ser-lys-leu) tripeptide at the C-terminus as a targeting sequence, and the import of at least one, acyl-CoA oxidase, is ATP-dependent. Peroxisomal membrane proteins (PMP), as well as the peroxisomal matrix enzymes, are synthesized on free cytoplasmic polysomes at their mature size. Disorders with defective peroxisome biogenesis include Zellweger syndrome (ZWS1; 214100) and neonatal adrenoleukodystrophy (202370). In these disorders, many peroxisomal matrix proteins are mislocated in the cytosol, whereas others, such as PMP70, PMP22 (601097), and thiolase precursor, are associated with irregularly shaped vesicles which may be defective peroxisomes or peroxisome precursors. These observations led to the hypothesis that the peroxisome biogenesis defects are due to defective import mechanisms for peroxisomal matrix enzymes. Somatic cell fusion studies indicated the existence of at least 11 complementation groups for ZS and related phenotypes (Moser et al., 1995). Gartner et al. (1992) described 2 point mutations in the PMP70 gene (PXMP1) in separate patients of the same complementation group. The functional significance of these mutations was not determined, although neither was present in over 100 controls. Subsequently, Gartner et al. (1994) showed that overexpression of PMP70 suppressed the cellular phenotype of mutations in the gene encoding PMP35 (170993), a second integral peroxisomal membrane protein, and that 1 of the PMP70 mutant alleles was unable to do this. Despite these results, the role of PMP70 in the causation of Zellweger syndrome remained uncertain. The patients of Gartner et al. (1992) belong to complementation group 1 (Kennedy-Krieger Institute Nomenclature). Paton et al. (1997) investigated 12 Australian patients of complementation group 1 for mutations in the PMP70 gene. The more severe phenotype of Zellweger syndrome was present in 8 of the patients, whereas the remaining 4 patients had the milder, infantile Refsum disease phenotype. Apart from a previously known synonymous polymorphism, no clear differences were observed on SSCP gels of DNA from these patients. These results are further evidence against a causative role for PMP70 in Zellweger syndrome. PMP70 was mapped to chromosome 1 by analysis of somatic cell hybrid DNAs (Gartner et al., 1992) and regionalized to 1p22-p21 by fluorescence in situ hybridization (Gartner et al., (1992, 1993)). The gene encoding the mouse homolog of PMP70 (Pmp1) was located on chromosome 3 by interspecific backcross analysis. PMP70 is a member of the ATP-binding cassette (ABC) transporter family, which predicts its direct involvement in the importing of peroxisomal matrix components into peroxisomes. Although the amino acid sequence of the C-terminal half of PMP70 is highly conserved with other ABC transporters such as CFTR (602421) and MDR (171050), the organization of the 3-prime exons is not similar to that in the genes for these other proteins. | ||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||
| Table View | ||||||||||||||||||
| .0001 ZELLWEGER SYNDROME 2 | ||||||||||||||||||
| ABCD3, IVS L-1, DS, G-A, +1, 23-BP INS | ||||||||||||||||||
| In a patient with Zellweger syndrome, Gartner et al. (1992) found a 23-bp insertion in PMP70 cDNA resulting from a G-to-A transition at the first nucleotide in the L-1 intron. (Since the entire gene structure was not known, the 3 most 3-prime exons of the PMP70 gene were referred to as L (for 'last'), L-1, and L-2.) The patient was a compound heterozygote. The nature of the other allele was not identified. Neither parent had the G-to-A mutation (paternity was confirmed by special testing); thus, the particular mutation was a new one. | ||||||||||||||||||
| .0002 ZELLWEGER SYNDROME 2 | ||||||||||||||||||
| ABCD3, GLY17ASP [dbSNP:rs121917999] | ||||||||||||||||||
| In a patient with Zellweger syndrome, Gartner et al. (1992) identified compound heterozygosity for a G-to-A transition at bp 50 of the cDNA coding for part of the PMP70 gene. This mutation changed codon 17 from GGT to GAT, resulting in the substitution of aspartic acid for glycine (G17D). The nature of the other mutation was not identified. The patient was the product of a nonconsanguineous union of a Caucasian woman and an African American man and was 1 of 2 affected sibs. | ||||||||||||||||||
| See Also: | ||||||||||||||||||
| Gartner et al. (1992) | ||||||||||||||||||
| REFERENCES | ||||||||||||||||||
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