Alternative titles; symbols
HGNC Approved Gene Symbol: ABCA2
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:137,007,234-137,028,922 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Intellectual developmental disorder with poor growth and with or without seizures or ataxia | 618808 | Autosomal recessive | 3 |
Members of the ABCA transporter subfamily, such as ABCA2, are involved in sterol transport (Ohtsuki et al., 2004).
Luciani et al. (1994) identified 2 members of the ATP-binding cassette gene family, ATP1 (ABCA1; 600046) and ATP2.
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Kikuno et al. (1999) cloned ABCA2, which they designated KIAA1062. The deduced 1,529-amino acid protein shares 94% identity with mouse Abc2. RT-PCR ELISA detected ABCA2 in all adult and fetal tissues examined. Highest expression was detected in whole adult and fetal brain and in all specific brain regions examined, including spinal cord. In descending order of abundance, ABCA2 was also detected in adult lung, kidney, heart, liver, ovary, skeletal muscle, pancreas, testis, and spleen and fetal liver.
Beginning with the partial 3-prime ABCA2 sequence represented by KIAA1062, followed by RT-PCR of macrophage RNA and 5-prime RACE of a spleen cDNA library, Kaminski et al. (2001) cloned full-length ABCA2. The deduced 2,436-amino acid protein shares 50% identity with ABCA1 and 44% identity with ABCA7 (605414).
Using RT-PCR, Ohtsuki et al. (2004) detected expression of ABCA2 and ABCA5 (612503) in cultured human brain capillary endothelial cells, which form the blood-brain barrier.
By PCR of neuroblastoma cell line total RNA, Ile et al. (2004) cloned 2 ABCA2 cDNAs with different 5-prime exons. Translation of the alternative 5-prime exons results in proteins with different N termini; exon 1B encodes 52 amino acids, and exon 1A encodes 22 amino acids. Real-time PCR detected variable expression of transcripts with exon 1A in all tissues examined, with highest levels in brain, ovary, and peripheral blood leukocytes. Transcripts with exon 1B were highly expressed in peripheral blood leukocytes, with weak or no expression in all other tissues examined. Following transfection of Chinese hamster ovary cells, both ABCA2 isoforms colocalized with lysosomal markers.
Kaminski et al. (2001) demonstrated that ABCA2 mRNA is induced in human macrophages during cholesterol import, indicating that ABCA2 is a cholesterol-responsive gene.
Ile et al. (2004) found that overexpression of ABCA2 in human embryonic kidney cells increased cellular resistance to the cytotoxic effects of acute estradiol and estramustine exposure. Elevated ABCA2 expression was also detected in an estramustine-resistant prostate carcinoma cell line. Chinese hamster ovary (CHO) cells transfected with a putative dominant-negative form of ABCA2, in which the conserved lysines in the Walker A motif of nucleotide-binding domains 1 and 2 were mutated, showed no changes in cytotoxicity for estramustine or estradiol.
Davis et al. (2004) found that CHO cells overexpressing human ABCA2 showed increased expression of low density lipoprotein receptor (LDLR; 606945) and HMG-CoA synthase (see HMGCS1; 142940) and reduced esterification of LDL-derived free cholesterol. Treatment of CHO cells with progesterone or the hydrophobic amine U18666A, which inhibit cholesterol synthesis and cause accumulation of LDL-derived cholesterol in lysosomes, elevated ABCA2 expression. ABCA2 expression was also elevated in Niemann-Pick type C1 (257220) fibroblasts and in familial hypercholesterolemia (143890) fibroblasts. Davis et al. (2004) concluded that ABCA2 may have a role in delivery of LDL-derived free cholesterol to the endoplasmic reticulum for esterification.
Chen et al. (2004) used amplified differential gene expression (ADGE) microarray analysis to study ABCA2-transfected human embryonic kidney cells. Among the 152 genes detected with greater than 3-fold changes in expression were those related to transport, oxidative stress responses, and beta-amyloid (APP; 104760) metabolism. In vitro studies showed that ABCA2 was highly expressed in human neuroblastoma cells and colocalized with beta-amyloid; overexpression of ABCA2 increased APP protein levels. ABCA2 was detected in the temporal and frontal cortex of both normal brains and brains of patients with Alzheimer disease (AD; 104300). ABCA2-transfected cells were more resistant to a free radical initiator, showing that ABCA2 is involved in protection against reactive oxygen species and suggesting a link to AD.
Kaminski et al. (2001) determined that the ABCA2 gene contains 48 exons and spans 21 kb. The 5-prime end contains a forward-oriented Alu repeat and binding sites for transcription factors with roles in the myeloid and neural system.
Ile et al. (2004) identified 2 alternate first exons, 1A and 1B, separated by 699 bp in the ABCA2 gene.
Luciani et al. (1994) mapped the ABC2 gene to chromosome 9q34 by isotopic in situ hybridization. The mouse Abc2 gene maps to mouse chromosome 2. They authors hypothesized that the ABC1 and ABC2 genes probably originated through a duplication event that took place before speciation.
By radiation hybrid analysis, Kikuno et al. (1999) mapped the ABCA2 gene to chromosome 9.
Intellectual Developmental Disorder with Poor Growth and with or without Seizures or Ataxia
In 2 unrelated patients, born of consanguineous parents, with intellectual developmental disorder with poor growth and seizures without ataxia (IDPOGSA; 618808), Maddirevula et al. (2019) identified homozygous putative loss-of-function mutations in the ABCA2 gene (600047.0001 and 600047.0002). The mutations, which were found by exome sequencing of a cohort of over 2,500 patients with various mendelian phenotypes, were not present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed.
In 3 sibs, born of consanguineous Iranian parents, with IDPOGSA, Hu et al. (2019) identified a homozygous frameshift mutation in the ABCA2 gene (600047.0003). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variant and studies of patient cells were not performed.
Associations Pending Confirmation
Mace et al. (2005) found a significant association between a C-T SNP in exon 14 of the ABCA2 gene (rs908832) and Alzheimer disease (AD; see 104300) in a large case-control study involving 440 AD patients. Additional analysis showed the strongest association between the SNP and early-onset AD (odds ratio of 3.82 for disease development in carriers of the T allele compared to control).
For discussion of a possible association between variation in the ABCA2 gene and a neurologic disorder with gait ataxia and dysarthria, see 618808 and 600047.0004.
Sakai et al. (2007) found that Abca2 -/- mice had no reduction in embryonic viability, were born at the expected mendelian ratio, and were fertile. However, Abca2 -/- mice displayed lower pregnancy rate and body weight, shorter latency period on balance beam, sensitization to environmental stress, and higher death rate after 1 week compared with wildtype mice. Histologic examination of Abca2 -/- brain showed no abnormalities in cytoarchitectonic and compact myelin structure or oligodendroglial differentiation and stability. Lipid analysis revealed that Abca2 -/- brain had accumulation of gangliosides along with reduced sphingomyelin (SM), and accumulation of cerebrosides and sulfatides. Further analysis showed accumulation of the major ganglioside GM1 and reduced SM in myelin fractions of Abca2 -/- brain. The results indicated that ABCA2 is involved in intracellular metabolism of sphingolipids in brain, particularly SM and gangliosides in oligodendrocytes and certain neurons.
In a 13-year-old girl (patient 16DG0071), born of consanguineous parents, with intellectual developmental disorder with poor growth and seizures without ataxia (IDPOGSA; 618808), Maddirevula et al. (2019) identified a homozygous c.1027C-T transition (c.1027C-T, NM_212533.2) in the ABCA2 gene, resulting in a gln343-to-ter (Q343X) substitution. The mutation, which was found by a combination of autozygosity mapping and exome sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 10-year-old boy (patient 16-2987), born of distantly related Saudi parents, with intellectual developmental disorder with poor growth and seizures without ataxia (IDPOGSA; 618808), Maddirevula et al. (2019) identified a homozygous 1-bp duplication (c.740dupT, NM_212533.2) in the ABCA2 gene, predicted to result in a frameshift and premature termination (Gly248ArgfsTer38). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 3 sibs, born of consanguineous Iranian parents (family M8600615), with intellectual developmental disorder with poor growth, seizures, and variable ataxia (IDPOGSA; 618808), Hu et al. (2019) identified a homozygous c.4537_4547del/insG (c.4537_4547delinsG, NM_001606) mutation in the ABCA2 gene, predicted to result in a frameshift and premature termination (Arg1513AlafsTer15). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variant and studies of patient cells were not performed.
This variant is classified as a variant of unknown significance because its contribution to a neurologic disorder with gait ataxia and dysarthria (see 618808) has not been confirmed.
In 2 brothers, born of consanguineous Pakistani parents (family RDFA01), with a neurologic disorder characterized by onset of gait ataxia and dysarthria in early childhood, Aslam and Naz (2019) identified a homozygous 1-bp deletion (c.4993delG, NM_212533.2) in exon 31 of the ABCA2 gene, predicted to result in a frameshift and premature termination (Val1665TyrfsTer36) affecting the second membrane-spanning domain of the protein. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, or in 100 ethnically matched controls. Analysis of patient cells showed presence of the mutant transcript, suggesting that the mutation may escape nonsense-mediated mRNA decay, but Western blot analysis and additional studies were not performed. Aslam and Naz (2019) noted that the c.4993delG variant may not be the cause of the disorder, but rather may be in linkage disequilibrium with the disease-causing variant.
Aslam, F., Naz, S. Ataxia and dysarthria due to an ABCA2 variant: extension of the phenotypic spectrum. Parkinsonism Relat. Disord. 64: 328-331, 2019. [PubMed: 31047799] [Full Text: https://doi.org/10.1016/j.parkreldis.2019.04.017]
Chen, Z. J., Vulevic, B., Ile, K. E., Soulika, A., Davis, W., Jr., Reiner, P. B., Connop, B. P., Nathwani, P., Trojanowski, J. Q., Tew, K. D. Association of ABCA2 expression with determinants of Alzheimer's disease. FASEB J. 18: 1129-1131, 2004. [PubMed: 15155565] [Full Text: https://doi.org/10.1096/fj.03-1490fje]
Davis, W., Jr., Boyd, J. T., Ile, K. E., Tew, K. D. Human ATP-binding cassette transporter-2 (ABCA2) positively regulates low-density lipoprotein receptor expression and negatively regulates cholesterol esterification in Chinese hamster ovary cells. Biochim. Biophys. Acta 1683: 89-100, 2004. [PubMed: 15238223] [Full Text: https://doi.org/10.1016/j.bbalip.2004.04.009]
Hu, H., Kahrizi, K., Musante, L., Fattahi, Z., Herwig, R., Hosseini, M., Oppitz, C., Abedini, S. S., Suckow, V., Larti, F., Beheshtian, M., Lipkowitz, B. Genetics of intellectual disability in consanguineous families. Molec. Psychiat. 24: 1027-1039, 2019. [PubMed: 29302074] [Full Text: https://doi.org/10.1038/s41380-017-0012-2]
Ile, K. E., Davis, W., Jr., Boyd, J. T., Soulika, A. M., Tew, K. D. Identification of a novel first exon of the human ABCA2 transporter gene encoding a unique N-terminus. Biochim. Biophys. Acta 1678: 22-32, 2004. [PubMed: 15093135] [Full Text: https://doi.org/10.1016/j.bbaexp.2004.01.007]
Kaminski, W. E., Piehler, A., Pullmann, K., Porsch-Ozcurumez, M., Duong, C., Bared, G. M., Buchler, C., Schmitz, G. Complete coding sequence, promoter region, and genomic structure of the human ABCA2 gene and evidence for sterol-dependent regulation in macrophages. Biochem. Biophys. Res. Commun. 281: 249-258, 2001. [PubMed: 11178988] [Full Text: https://doi.org/10.1006/bbrc.2001.4305]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Luciani, M. F., Denizot, F., Savary, S., Mattei, M. G., Chimini, G. Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics 21: 150-159, 1994. [PubMed: 8088782] [Full Text: https://doi.org/10.1006/geno.1994.1237]
Mace, S., Cousin, E., Ricard, S., Genin, E., Spanakis, E., Lafargue-Soubigou, C., Genin, B., Fournel, R., Roche, S., Haussy, G., Massey, F., Soubigou, S., Brefort, G., Benoit, P., Brice, A., Campion, D., Hollis, M., Pradier, L., Benavides, J., Deleuze, J.-F. ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease. Neurobiol. Dis. 18: 119-125, 2005. [PubMed: 15649702] [Full Text: https://doi.org/10.1016/j.nbd.2004.09.011]
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Ohtsuki, S., Watanabe, Y., Hori, S., Suzuki, H., Bhongsatiern, J., Fujiyoshi, M., Kamoi, M., Kamiya, N., Takanaga, H., Terasaki, T. mRNA expression of the ATP-binding cassette transporter subfamily A (ABCA) in rat and human brain capillary endothelial cells. Biol. Pharm. Bull. 27: 1437-1440, 2004. [PubMed: 15340233] [Full Text: https://doi.org/10.1248/bpb.27.1437]
Sakai, H., Tanaka, Y., Tanaka, M., Ban, N., Yamada, K., Matsumura, Y., Watanabe, D., Sasaki, M., Kita, T., Inagaki, N. ABCA2 deficiency results in abnormal sphingolipid metabolism in mouse brain. J. Biol. Chem. 282: 19692-19699, 2007. [PubMed: 17488728] [Full Text: https://doi.org/10.1074/jbc.M611056200]