Alternative titles; symbols
HGNC Approved Gene Symbol: ABCD4
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:74,285,269-74,302,934 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Methylmalonic aciduria and homocystinuria, cblJ type | 614857 | Autosomal recessive | 3 |
The ABCD4 gene encodes a protein with several transmembrane domains and ATPase function. There is a cytosolic nucleotide (ATP)-binding domain with highly conserved motifs at the C terminus. The protein is involved in the intracellular processing of cobalamin (vitamin B12) (summary by Coelho et al., 2012).
The peroxisomal membrane contains several ATP-binding cassette (ABC) transporters, including PMP70 (ABCD3; 170995), ALDP (ABCD1; 300371), and ALDR (ABCD2; 601081). All 3 proteins are ABC half-transporters, which dimerize to form an active transporter. See 603076. By searching an EST database for homologs of PMP70 and ALDP, Shani et al. (1997) and Holzinger et al. (1997) identified PXMP1L cDNAs. They respectively designated the gene P70R and PMP69. Shani et al. (1997) reported that the predicted 606-amino acid protein has the structure of an ABC half-transporter and shares 25 to 27% sequence identity with PMP70, ALDR, and ALDP. Antibodies against PXMP1L detected a 73-kD protein on Western blots. Immunofluorescence studies localized the protein to peroxisomes. Northern blot analysis revealed that PXMP1L was expressed as a 2.6-kb mRNA in all tissues examined. Holzinger et al. (1997) and Holzinger et al. (1998) found transcript variants resulting from alternative splicing and use of alternative polyadenylation sites.
Holzinger et al. (1998) reported that the PXMP1L gene contains 19 exons and spans approximately 16 kb.
By analysis of a somatic cell hybrid panel and by identity with mapped clones, Shani et al. (1997) mapped the PXMP1L gene to 14q24. Holzinger et al. (1998) confirmed this localization by fluorescence in situ hybridization. They noted that part of a PXMP1L cDNA was included in a cosmid derived from chromosome 14q24.3.
Coelho et al. (2012) demonstrated that ABCD4 colocalized with the lysosomal proteins LAMP1 (153330) and LMBRD1 (612625), the latter of which is deficient in methylmalonic aciduria and homocystinuria, type cblF (MAHCF; 277380). Cellular studies with mutant ABCD4 alleles indicated that the ATPase domain of ABCD4 may be involved in the intracellular processing of vitamin B12 (cobalamin). The biochemical findings and localization studies suggested that ABCD4 is involved in the lysosomal release of cbl into the cytoplasm. Although ABCD4 was initially thought to be a peroxisomal protein, Coelho et al. (2012) provided evidence against the involvement of peroxisomes in cbl metabolism.
Using immunoprecipitation and confocal microscopy analyses in human hepatoma and embryonic kidney cells and Chinese hamster ovary cells, Kawaguchi et al. (2016) demonstrated that ABCD4 interacted with LMBD1 (LMBRD1; 612625) and then localized to lysosomes in a manner dependent on the lysosome targeting ability of LMBD1. Knockout of LMBRD1 disturbed ABCD4 localization to lysosomes, but not to the endoplasmic reticulum (ER). Kawaguchi et al. (2016) concluded that translocation of ABCD4 from the ER to lysosomes requires, at least in part, LMBD1.
Methylmalonic Aciduria and Homocystinuria, cblJ Type
In 2 unrelated children with methylmalonic aciduria and homocystinuria type cblJ (MAHCJ; 614857), Coelho et al. (2012) identified 4 different mutations in the ABCD4 gene (603214.0001-603214.0004) in compound heterozygous state. The mutations, which were found using microcell-mediated chromosome transfer and exome sequencing, resulted in a loss of function. The patients presented soon after birth with hypotonia, respiratory distress, and evidence of bone marrow failure. One child had mild dysmorphic features, cardiac abnormalities, and delayed psychomotor development. Biochemical studies confirmed a defect in cobalamin metabolism and were similar to abnormalities observed in patients with cblF (277380). Patient cell lines showed no rescue of the defect when transfected with LMBRD1 (612625), suggesting that these 2 genes function in the same pathway.
Kitai et al. (2021) expressed ABCD4 and LMBRD1 on the surface of cobalamin-loaded liposomes to examine their roles in lysosomal cobalamin transport. ABCD4 transported cobalamin from the inside to the outside of the liposomes in an ATP-dependent manner, whereas LMBRD1 had no cobalamin transport activity. Kitai et al. (2021) concluded that ABCD4 may have a cellular role in transporting cobalamin from the lysosome to the cytosol. Kitai et al. (2021) also studied the effects of several ABCD4 missense mutations identified in individuals with MAHJC to determine their mechanism of pathogenicity. R432Q, located on or close to the Walker A motif, had reduced ATPase activity compared to wildtype. N141K, located on the cytosolic side the TM3 motif, lacked cobalamin transport activity. Y319C (603214.0001), located in the lysosomal side of the TM6 motif, lacked both cobalamin transport and ATPase activity.
Expression of ABCD4 in Adrenoleukodystrophy
Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN), and AMN with cerebral demyelination are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD; 300100), which is caused by mutation in the ABCD1 gene (300371). The biochemical hallmark of ALD is the accumulation of very long chain fatty acids (VLCFA) in plasma and tissues. Asheuer et al. (2005) studied the expression of the ABCD1, ABCD2, ABCD3 (170995), and ABCD4 genes and 2 VLCFA synthetase genes, VLCS (SLC27A2; 603247) and BG1 (ACSBG1; 614362), in fibroblasts and brains from normal controls and ALD patients with the 3 main phenotypes, and they studied VLCFA concentrations in normal-appearing white matter from ALD patients with the 3 main phenotypes. The authors showed that ABCD1-truncating mutations were unlikely to cause variation in the ALD phenotype. Accumulation of saturated VLCFA in normal-appearing white matter correlated with ALD phenotype. Expression of ABCD4 and BG1, but not of the ABCD2, ABCD3, and VLCS genes, tended to correlate with the severity of the disease, acting early in the pathogenesis of ALD.
In a North American child with methylmalonic aciduria and homocystinuria of complementation group J (MAHCJ; 614857), Coelho et al. (2012) identified compound heterozygosity for 2 mutations in the ABCD4 gene: a 956A-G transition resulting in a tyr319-to-cys (Y319C) substitution in the last transmembrane domain, and a 2-bp insertion (1746insCT; 603214.0001), resulting in a frameshift and premature termination (Glu583LeufsTer9) leading to the removal of 14 residues from the C terminus in the predicted cytosolic nucleotide binding domain. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for one of the mutations. Neither mutation was found in the 1000 Genomes Project database. Expression of wildtype ABCD4 in patient fibroblasts led to rescue of the biochemical phenotype.
For discussion of the 2-bp insertion (1746insCT) in the ABCD4 gene that was found in compound heterozygous state in a child with methylmalonic aciduria and homocystinuria (MAHCJ; 614857) by Coelho et al. (2012), see 603214.0001.
In a European child with methylmalonic aciduria and homocystinuria, complementation group J (MAHCJ; 614857), Coelho et al. (2012) identified compound heterozygosity for 2 splice site mutations in the ABCD4 gene: a G-T transversion in intron 5 (542+1G-T), resulting in the skipping of exon 5 (D143_S181del), which encodes one of the transmembrane domains, and a 1456G-T transversion at the last nucleotide in exon 14, resulting in the skipping of exons 13 and 14 (G443_S485del; 603214.0004) in the cytosolic nucleotide binding domain. The mutations were identified by microcell-mediated chromosome transfer and exome sequencing. Neither mutation was found in the 1000 Genomes Project database. Expression of wildtype ABCD4 in patient fibroblasts led to rescue of the biochemical phenotype.
For discussion of the 1456G-T transversion at the last nucleotide in exon 14 of the ABCD4 gene that was found in compound heterozygous state in a child with methylmalonic aciduria and homocystinuria (MAHCJ; 614857) by Coelho et al. (2012), see 603214.0003.
Asheuer, M., Bieche, I., Laurendeau, I., Moser, A., Hainque, B., Vidaud, M., Aubourg, P. Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy. Hum. Molec. Genet. 14: 1293-1303, 2005. [PubMed: 15800013] [Full Text: https://doi.org/10.1093/hmg/ddi140]
Coelho, D., Kim, J. C., Miousse, I. R., Fung, S., du Moulin, M., Buers, I., Suormala, T., Burda, P., Frapolli, M., Stucki, M., Nurnberg, P., Thiele, H., and 12 others. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nature Genet. 44: 1152-1155, 2012. [PubMed: 22922874] [Full Text: https://doi.org/10.1038/ng.2386]
Holzinger, A., Kammerer, S., Roscher, A. A. Primary structure of human PMP69, a putative peroxisomal ABC-transporter. Biochem. Biophys. Res. Commun. 237: 152-157, 1997. [PubMed: 9266848] [Full Text: https://doi.org/10.1006/bbrc.1997.7102]
Holzinger, A., Roscher, A. A., Landgraf, P., Lichtner, P., Kammerer, S. Genomic organization and chromosomal localization of the human peroxisomal membrane protein-1-like protein (PXMP1-L) gene encoding a peroxisomal ABC transporter. FEBS Lett. 426: 238-242, 1998. [PubMed: 9599016] [Full Text: https://doi.org/10.1016/s0014-5793(98)00354-8]
Kawaguchi, K., Okamoto, T., Morita, M., Imanaka, T. Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1. Sci. Rep. 6: 30183, 2016. Note: Electronic Article. [PubMed: 27456980] [Full Text: https://doi.org/10.1038/srep30183]
Kitai, K., Kawaguchi, K., Tomohiro, T., Morita, M., So, T., Imanaka, T. The lysosomal protein ABCD4 can transport vitamin B-12 across liposomal membranes in vitro. J. Biol. Chem. 296: 100654, 2021. [PubMed: 33845046] [Full Text: https://doi.org/10.1016/j.jbc.2021.100654]
Shani, N., Jimenez-Sanchez, G., Steel, G., Dean, M., Valle, D. Identification of a fourth half ABC transporter in the human peroxisomal membrane. Hum. Molec. Genet. 6: 1925-1931, 1997. [PubMed: 9302272] [Full Text: https://doi.org/10.1093/hmg/6.11.1925]