Alternative titles; symbols
HGNC Approved Gene Symbol: ACBD5
Cytogenetic location: 10p12.1 Genomic coordinates (GRCh38): 10:27,182,838-27,242,111 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.1 | Retinal dystrophy with leukodystrophy | 618863 | Autosomal recessive | 3 |
Acyl-CoA-binding proteins, such as ACBD5, function in the sequestration, transport, and distribution of long-chain acyl-CoAs and can function as signaling molecules involved in cell metabolism and gene regulation (Punzo et al., 2010).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Ohara et al. (2002) obtained a partial ACBD5 clone, which they designated KIAA1996. The deduced 437-amino acid sequence shares significant identity with the Bos taurus endozepine-related protein precursor. RT-PCR ELISA detected variable KIAA1996 expression in all adult and fetal tissues examined, with highest level in adult brain. Expression was detected in all specific adult brain regions examined and was highest in substantia nigra.
Punzo et al. (2010) reported that ACBD5 has a predicted molecular mass of 54.7 kD. Quantitative RT-PCR detected ACBD5 expression in all normal blood cell types examined.
Yagita et al. (2017) reported that human ACBD5 isoform 2 contains 490 amino acids. It has an acyl-CoA-binding domain (ACBD) at its N terminus and a coiled-coil domain and a single transmembrane domain at its C terminus.
Punzo et al. (2010) determined that the ACBD5 gene contains 13 exons.
Punzo et al. (2010) stated that the ACBD5 gene maps between markers D10S586 and D20S611, which localize to chromosome 10p12.1 (Hartz, 2015).
Yagita et al. (2017) showed that human ACBD5 was a peroxisomal membrane protein with the N-terminal ACBD exposed to the cytosol and the C-terminal single transmembrane domain mediating peroxisomal targeting and membrane anchoring. Absence of ACBD5 did not affect biogenesis of peroxisomes in human skin fibroblasts, but it impaired peroxisomal beta-oxidation of very long chain fatty acids (VLCFAs). Knockout analysis in HeLa cells demonstrated that ACBD5 preferentially bound to VLC-CoAs and directly mediated peroxisomal beta-oxidation of VLCFAs, for which ACBD and peroxisomal localization of ACBD5 were essential.
Ferdinandusse et al. (2017) used CRISPR-Cas9 gene editing to introduce ACBD5 deficiency in HeLa cells, and observed an abnormal VLCFA profile, with increased C26:0 levels and an increased C26:0/C22:0 ratio, as well as increased C26:0 lysophosphatidylcholine. In addition, C26:0 beta-oxidation activity was reduced in the ACBD5-deficient HeLa cells, and loading with D3-C22:0 resulted in accumulation of D3-C26:0. The authors concluded that deficiency of ACBD5 results in impaired peroxisomal VLCFA metabolism.
In 3 sibs from a consanguineous Saudi family with retinal dystrophy and leukodystrophy (RDLKD; 618863), Abu-Safieh et al. (2013) identified homozygosity for a splicing mutation in the ACBD5 gene (616618.0001) that segregated with disease and was not found in 160 Saudi exomes, 190 controls, or in the Exome Variant Server database.
In a girl from the United Arab Emirates with retinal dystrophy and leukodystrophy, who exhibited impaired peroxisomal beta-oxidation of C26:0 but was negative for mutation in the ACOX1 (609751) and ABCD1 (300371) genes, Ferdinandusse et al. (2017) sequenced the candidate gene ACBD5 and identified homozygosity for a deletion/insertion mutation (616618.0002) that segregated with disease in the family.
Although Punzo et al. (2010) identified a heterozygous missense variant in the ACBD5 gene (H8Y) in a large Italian family (family R) with autosomal dominant thrombocytopenia (see THC2, 188000) linked to chromosome 10p12, Pippucci et al. (2011) determined that the disorder in this family was caused by a heterozygous mutation in the promoter region of the ANKRD26 gene on chromosome 10p12-p11.1 (610855.0001).
In 3 sibs from a consanguineous Saudi family (CRSPW) who had retinal dystrophy with leukodystrophy (RDLKD; 618863), Abu-Safieh et al. (2013) identified homozygosity for a splice donor site transition (c.1205+1G-A, NM_145698.3) in the ACBD5 gene, predicted to cause a frameshift resulting in a premature termination codon (Gly402AspfsTer5). The mutation segregated with disease in the family and was not found in 160 Saudi exomes, 190 directly sequenced Saudi controls, or the Exome Variant Server database. Western blot analysis showed no evidence of the expected smaller band representing the truncated protein, suggesting that the mutation causes severe instability of the protein and can thus be considered as a null allele.
In a girl from the United Arab Emirates with retinal dystrophy and leukodystrophy (RDLKD; 618863), Ferdinandusse et al. (2017) identified homozygosity for a deletion/insertion mutation (c.626-689_937-234delins936+1075_c.936+1230inv), causing deletion of exons 7 and 8 and predicted to result in a premature termination codon (Asp208ValfsTer30). Her consanguineous parents were both heterozygous for the mutation. Immunoblot and immunofluorescence analysis demonstrated the absence of ACBD5 in patient fibroblasts. In patient fibroblasts transfected with wildtype ACBD5, impaired very long chain fatty acid (VLCFA) metabolism was rescued, with significant reductions in levels of C26:0 lysophosphatidylcholine, D3-C28:0, and D3-C26:0, as well as a significant reduction in unlabeled C26:0 and a decrease in the C26:0/C22:0 ratio.
Abu-Safieh, L., Alrashed, M., Anazi, S., Alkuraya, H., Khan, A. O., Al-Owain, M., Al-Zahrani, J., Al-Abdi, L., Hashem, M., Al-Tarimi, S., Sebai, M.-A., Shamia, A., and 9 others. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 23: 236-247, 2013. [PubMed: 23105016] [Full Text: https://doi.org/10.1101/gr.144105.112]
Ferdinandusse, S., Falkenberg, K. D., Koster, J., Mooyer, P. A., Jones, R., van Roermund, C. W. T., Pizzino, A., Schrader, M., Wanders, R. J. A., Vanderver, A., Waterham, H. R. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J. Med. Genet. 54: 330-337, 2017. [PubMed: 27799409] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104132]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/26/2015.
Ohara, O., Nagase, T., Mitsui, G., Kohga, H., Kikuno, R., Hiraoka, S., Takahashi, Y., Kitajima, S., Saga, Y., Koseki, H. Characterization of size-fractionated cDNA libraries generated by the in vitro recombination-assisted method. DNA Res. 9: 47-57, 2002. [PubMed: 12056414] [Full Text: https://doi.org/10.1093/dnares/9.2.47]
Pippucci, T., Savoia, A., Perrotta, S., Pujol-Moix, N., Noris, P., Castegnaro, G., Pecci, A., Gnan, C., Punzo, F., Marconi, C., Gherardi, S., Loffredo, G., and 11 others. Mutations in the 5-prime UTR of ANKRD26, the ankirin (sic) repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am. J. Hum. Genet. 88: 115-120, 2011. [PubMed: 21211618] [Full Text: https://doi.org/10.1016/j.ajhg.2010.12.006]
Punzo, F., Mientjes, E. J., Rohe, C. F., Scianguetta, S., Amendola, G., Oostra, B. A., Bertoli-Avella, A. M., Perrotta, S. A mutation in the acyl-coenzyme A binding domain-containing protein 5 gene (ACBD5) identified in autosomal dominant thrombocytopenia. J. Thromb. Haemost. 8: 2085-2087, 2010. [PubMed: 20626622] [Full Text: https://doi.org/10.1111/j.1538-7836.2010.03979.x]
Yagita, Y., Shinohara, K., Abe, Y., Nakagawa, K., Al-Owain, M., Alkuraya, F. S., Fujiki, Y. Deficiency of a retinal dystrophy protein, acyl-CoA binding domain-containing 5 (ACBC5), impairs peroxisomal beta-oxidation of very-long-chain fatty acids. J. Biol. Chem. 292: 691-705, 2017. [PubMed: 27899449] [Full Text: https://doi.org/10.1074/jbc.M116.760090]