Alternative titles; symbols
HGNC Approved Gene Symbol: ABCD3
Cytogenetic location: 1p21.3 Genomic coordinates (GRCh38): 1:94,385,131-94,518,663 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p21.3 | ?Bile acid synthesis defect, congenital, 5 | 616278 | Autosomal recessive | 3 |
The ABCD3 gene encodes a peroxisomal membrane transporter involved in the transport of branched-chain fatty acids and C27 bile acids into the peroxisome; the latter function is a crucial step in bile acid biosynthesis (summary by Ferdinandusse et al., 2015).
By screening a human cDNA library with a fragment of rat Pmp70 cDNA, followed by RT-PCR and 5-prime and 3-prime RACE, Gartner et al. (1992) obtained a full-length human PMP70 cDNA. The 659-amino acid human protein is 95% identical to that of rat. The C-terminal portion is hydrophilic and contains 2 consensus sequences characteristic of a nucleotide-binding fold highly conserved in ATP-binding cassette (ABC) proteins.
Gartner et al. (1994) showed that overexpression of PMP70 suppressed the cellular phenotype of mutations in the gene encoding PMP35 (PEX2; 170993), another integral peroxisomal membrane protein, and that a PMP70 mutant allele was unable to do this.
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.
In a girl with congenital bile acid synthesis defect-5 (CBAS5; 616278), Ferdinandusse et al. (2015) identified a homozygous truncating mutation in the ABCD3 gene (170995.0003). Each unaffected parent was heterozygous for the mutation. The ABCD3 gene was chosen for study after laboratory studies suggested a defect in peroxisomal function, and immunofluorescent studies of patient peroxisomes showed absence of ABCD3 in the peroxisomal membrane. Transfection of wildtype ABCD3 in patient fibroblasts restored abnormal peroxisomal morphology. The patient presented in infancy with progressive liver disease that was ultimately fatal.
Ferdinandusse et al. (2015) found that newborn Abcd3-null mice showed normal activity and had no obvious malformations. However, necroscopy showed increased liver size compared to controls, and fibroblasts showed reduced numbers of enlarged peroxisomes. Laboratory studies showed bile acid abnormalities, including a significant reduction in mature C24 bile acids, an increase in unconjugated bile acids, and an accumulation of C26-bile acid intermediates (DHCA and THCA). These findings were consistent with a defect in bile acid biosynthesis. Further studies showed that the Abcd3-null mice had impaired beta-oxidation of the branched-chain pristanic and phytanic fatty acids on a phytol-loaded diet.
This variant, formerly titled ZELLWEGER SYNDROME 2, has been reclassified based on the findings of Paton et al. (1997) and Collins and Gould (1999).
In a patient with Zellweger syndrome of complementation group 1, 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 mutation was identified on 1 allele only. The functional significance of this mutation was not determined.
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 provided evidence against a causative role for PMP70 in Zellweger syndrome.
Collins and Gould (1999) restudied the patient with CG1 Zellweger syndrome in whom Gartner et al. (1992) had found a 23-bp insertion in the PMP70 gene, and identified compound heterozygosity for a frameshift mutation (602136.0004) and a nonsense mutation in the PEX1 gene.
This variant, formerly titled ZELLWEGER SYNDROME 2, has been reclassified based on the findings of Paton et al. (1997) and Collins and Gould (1999).
In a patient with Zellweger syndrome of complementation group 1, Gartner et al. (1992) identified 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.
Paton et al. (1997) investigated 12 Australian patients of complementation group 1 for mutations in the PMP70 gene. Apart from a previously known synonymous polymorphism, no clear differences were observed on SSCP gels of DNA from these patients. These results provided evidence against a causative role for PMP70 in Zellweger syndrome.
The PEX1 gene (602136) was found to be the site of mutations resulting in peroxisomal biogenesis disorders of complementation group 1. Collins and Gould (1999) identified a heterozygous frameshift mutation in the PEX1 gene in this patient. The second mutation in this patient was not identified.
Collins and Gould (1999) restudied the patient with CG1 Zellweger syndrome in whom Gartner et al. (1992) had found a G17D variant in the PMP70 gene, and identified a heterozygous frameshift mutation mutation in the PEX1 gene. A second PEX1 mutation in this patient was not detected.
In a girl, born of consanguineous Turkish parents, with congenital bile acid synthesis defect-5 (CBAS5; 616278), Ferdinandusse et al. (2015) identified a homozygous 1,758-bp deletion encompassing exon 24 and part of the 3-prime untranslated region of the ABCD3 gene (c.1903-573_*1246, NM_002858.3), resulting in a truncated protein lacking the 24 C-terminal amino acids (Tyr635AsnfsTer1). The unaffected parents were heterozygous for the deletion; immunofluorescence studies of patient cells confirmed expression of a truncated protein. Patient fibroblasts showed a reduced number of enlarged peroxisomes, and this abnormality was reduced by expression of wildtype ABCD3.
Collins, C. S., Gould, S. J. Identification of a common PEX1 mutation in Zellweger syndrome. Hum. Mutat. 14: 45-53, 1999. [PubMed: 10447258] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)14:1<45::AID-HUMU6>3.0.CO;2-J]
Ferdinandusse, S., Jimenez-Sanchez, G., Koster, J., Denis, S., Van Roermund, C. W., Silva-Zolezzi, I., Moser, A. B., Visser, W. F., Gulloglu, M., Durmaz, O., Demirkol, M., Waterham, H. R., Gokcay, G., Wanders, R. J. A., Valle, D. A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. Hum. Molec. Genet. 24: 361-370, 2015. [PubMed: 25168382] [Full Text: https://doi.org/10.1093/hmg/ddu448]
Gartner, J., Kearns, W., Pearson, P., Valle, D. Characterization and localization of the human 70-kD peroxisomal membrane protein (PMP70) gene. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A168, 1992.
Gartner, J., Kearns, W., Rosenberg, C., Pearson, P., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Valle, D. Localization of the 70-kDa peroxisomal membrane protein to human 1p21-p22 and mouse 3. Genomics 15: 412-414, 1993. [PubMed: 8449508] [Full Text: https://doi.org/10.1006/geno.1993.1076]
Gartner, J., Moser, H., Valle, D. Mutations in the 70K peroxisomal membrane protein gene in Zellweger syndrome. Nature Genet. 1: 16-23, 1992. [PubMed: 1301993] [Full Text: https://doi.org/10.1038/ng0492-16]
Gartner, J., Obie, C., Watkins, P., Valle, D. Restoration of peroxisome biogenesis in a peroxisome-deficient mammalian cell line by expression of either the 35 kDa or the 70 kDa peroxisomal membrane proteins. J. Inherit. Metab. Dis. 17: 327-329, 1994. [PubMed: 7528830] [Full Text: https://doi.org/10.1007/BF00711820]
Paton, B. C., Heron, S. E., Nelson, P. V., Morris, C. P., Poulos, A. Absence of mutations raises doubts about the role of the 70-kD peroxisomal membrane protein in Zellweger syndrome. (Letter) Am. J. Hum. Genet. 60: 1535-1539, 1997. [PubMed: 9199576] [Full Text: https://doi.org/10.1016/S0002-9297(07)64247-5]