HGNC Approved Gene Symbol: ABCA12
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:214,931,542-215,138,626 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Ichthyosis, congenital, autosomal recessive 4A | 601277 | Autosomal recessive | 3 |
| Ichthyosis, congenital, autosomal recessive 4B (harlequin) | 242500 | Autosomal recessive | 3 |
Members of the ATP-binding cassette (ABC) transporter superfamily carry out energy-dependent transport of substrate molecules. ABCA12 belongs to a subfamily of ABC transporters that contain 2 transmembrane (TM) domains, each with about 6 membrane-spanning segments, and 2 nucleotide-binding domains (NBDs), which are located in the cytoplasm (Annilo et al., 2002).
Using the conserved domains of the ABCA subfamily to search an EST database, followed by 3-prime RACE of a placenta cDNA library, Annilo et al. (2002) cloned ABCA12. The deduced 2,595-amino acid protein has a putative 45-amino acid signal peptide at its N terminus and a domain structure typical of ABCA transporters. The 3-prime region contains 2 putative polyadenylation signals, and there is a possible alternative splice variant with an in-frame deletion leading to truncation of 79 amino acids. ABCA12 shares 36% sequence identity with ABCA1 (600046) and ABCA7 (605414), with highest similarity in their ATP-binding domains. Northern blot analysis detected low expression of ABCA12 in stomach and trace expression in colon, but not in any other tissue examined. RT-PCR detected expression in placenta, testis, fetal brain, and skin.
Annilo et al. (2002) determined that the ABCA12 gene contains 53 exons and spans 206 kb.
By radiation hybrid analysis, Annilo et al. (2002) mapped the ABCA12 gene to chromosome 2q34. By genomic sequence analysis, they mapped the mouse Abca12 gene to a region of chromosome 1 that shows homology of synteny to human chromosome 2q34.
Akiyama et al. (2005) demonstrated that ABCA12 is expressed in normal human keratinocytes and that this expression is upregulated during keratinization. Immunoelectron microscopy revealed that ABCA12 protein localizes to lamellar granules in the upper epidermal keratinocytes of human skin.
Congenital Ichthyosis 4A, Autosomal Recessive
Autosomal recessive congenital ichthyosis-4A (ARCI4A; 601277) is a rare skin disorder for which a locus, formerly designated LI2, was mapped to chromosome 2q33-q35. Lefevre et al. (2003) identified 5 missense mutations in the ABCA12 gene (607800.0001-607800.0005) among 9 African families with congenital ichthyosis of the lamellar type; 4 families were from Morocco, 4 from Algeria, and 1 from Mali. The mutations were homozygous in 8 consanguineous families and heterozygous in 1 nonconsanguineous family. Four of these mutations were localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABC proteins. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3 (601615), a lamellar body membrane protein in lung alveolar type II cells, the authors hypothesized that ABCA12 may function in cellular lipid trafficking in keratinocytes.
Congenital Ichthyosis 4B, Autosomal Recessive
Harlequin ichthyosis (ARCI4B; 242500) is the most severe and frequently lethal form of autosomal recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation had been described, the genetic basis was unknown. Using SNP chip technology and homozygosity mapping, Kelsell et al. (2005) identified a common region of homozygosity in the chromosomal region 2q35 in 5 patients with harlequin ichthyosis. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with harlequin ichthyosis (see, e.g., 607800.0006-607800.0009). Since harlequin ichthyosis epidermis displays abnormal lamellar granule formation, the authors suggested that ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder.
In 5 patients with harlequin ichthyosis from 4 unrelated families, Akiyama et al. (2005) identified either compound heterozygosity or homozygosity for 5 mutations in the ABCA12 gene. All of the mutations resulted in truncation or deletion of highly conserved regions of ABCA12. Ultrastructural and immunofluorescent examination of human skin and cultured epidermal keratinocytes from affected individuals showed defective lipid secretion of lamellar granule lipid contents; corrective gene transfer of ABCA12 restored the normal ability of the cultured cells to secrete lamellar granule lipid. Akiyama et al. (2005) concluded that ABCA12 works as an epidermal keratinocyte lipid transporter and that defective ABCA12 results in a loss of the skin lipid barrier, leading to harlequin ichthyosis.
Thomas et al. (2006) sequenced the ABCA12 gene in 14 patients with harlequin ichthyosis and identified mutations in all of them: 9 patients were homozygotes, 2 were compound heterozygotes, and in 3 patients, mutations were found on only 1 allele. The authors noted that the vast majority of ABCA12 mutations associated with harlequin ichthyosis are predicted to result in a truncated protein, although 1 patient was homozygous for a missense mutation (607800.0010). In a Caucasian British child born with severe ichthyosiform erythroderma, in whom Kelsell et al. (2005) did not identify any mutations by sequencing of the ABCA12 gene, Thomas et al. (2006) used a combination of oligonucleotide arrays, multiplex PCR analysis, and SNP genotyping to identify a heterozygous deletion (607800.0011). Thomas et al. (2006) concluded that ABCA12 is the major harlequin ichthyosis gene.
Akiyama (2010) reviewed mutations in the ABCA12 gene and stated that a total of 56 mutations had been reported in 66 ARCI families, including 48 with ichthyosis of the harlequin type (HI), 10 with congenital ichthyosis of the lamellar type (LI), and 8 with ichthyosis of the congenital ichthyosiform erythroderma (CIE) type. Most of the mutations in HI patients were truncation mutations, and homozygosity or compound heterozygosity for truncating mutations in ABCA12 always resulted in the HI phenotype. In CIE families, at least 1 mutation on each allele was typically a missense mutation, and combinations of missense mutations in the first ATP-binding cassette of ABCA12 caused the LI phenotype.
In 3 affected sibs from a consanguineous Moroccan family with congenital ichthyosis (ARCI4A; 601277) of the lamellar type, originally reported by Parmentier et al. (1996), Lefevre et al. (2003) identified homozygosity for a 4142G-A transition in the ABCA12 gene. The mutation was predicted to result in a gly1381-to-glu (G1381E) substitution in the nucleotide-binding fold (NBF1) domain. The mutation was not found in 100 North African control chromosomes.
In 3 affected individuals from 3 consanguineous Moroccan families with congenital ichthyosis (ARCI4A; 601277) of the lamellar type, 1 of which was originally reported by Parmentier et al. (1996) and 2 of which were previously studied by Parmentier et al. (1999), as well as a similarly affected individual from a consanguineous Algerian family, Lefevre et al. (2003) identified homozygosity for a 4139A-G transition in the ABCA12 gene. The mutation was predicted to result in an asn1380-to-ser (N1380S) substitution in the nucleotide-binding fold (NBF1) domain.
In 3 sibs with lamellar ARCI from a nonconsanguineous Algerian family, previously studied by Parmentier et al. (1999), Lefevre et al. (2003) identified compound heterozygosity for the N1380S mutation and another ABCA12 missense mutation, G1651S (607800.0003). Neither mutation was found in 100 North African control chromosomes. A common haplotype was found in 4 of the 5 families carrying the N1380S mutation, including 2 of the Moroccan families and both Algerian families, suggesting a founder effect.
In 3 sibs from a consanguineous Algerian family with congenital ichthyosis (ARCI4A; 601277) of the lamellar type, previously studied by Parmentier et al. (1999), Lefevre et al. (2003) identified homozygosity for a 4951G-A transition in the ABCA12 gene. The mutation was predicted to result in a gly1651-to-ser (G1651S) substitution in a cytoplasmic portion of the protein linking the first nucleotide-binding fold (NBF1) domain to the second transmembrane domain.
In 3 sibs with lamellar ARCI from a nonconsanguineous Algerian family previously studied by Parmentier et al. (1999), Lefevre et al. (2003) identified compound heterozygosity for the G1651 mutation and another ABCA12 missense mutation, N1380S (607800.0002). The compound heterozygous Algerian family shared a common haplotype on 1 allele with the consanguineous Algerian family, suggesting a founder effect. Neither mutation was found in 100 North African control chromosomes.
In an affected individual from a consanguineous Malian family with congenital ichthyosis (ARCI4A; 601277) of the lamellar type, Lefevre et al. (2003) identified homozygosity for a 4541G-A transition in the ABCA12 gene. The mutation was predicted to result in an arg1514-to-his (R1514H) substitution in the nucleotide-binding fold (NBF1) domain. The mutation was not found in 100 North African control chromosomes.
In a female patient from a consanguineous Algerian family with congenital ichthyosis (ARCI4A; 601277), Lefevre et al. (2003) identified homozygosity for a 4615G-A transition in the ABCA12 gene. The mutation was predicted to result in a glu1539-to-lys (E1539K) substitution in the nucleotide-binding fold (NBF1) domain. The mutation was not found in 100 North African control chromosomes. In contrast to other reported ARCI patients with ABCA12 mutations, this patient presented a milder form of ichthyosis with smaller whitish scales; she also had leukonychia and clubbing of the nails, and deformation of the second phalanx of the hands and feet.
In 3 patients of British Pakistani ethnicity and 1 of British Indian ancestry with harlequin ichthyosis (ARCI4B; 242500), Kelsell et al. (2005) found homozygosity for a frameshift mutation, 7541delC, in exon 49 of the ABCA12 gene. The frameshift resulted in a truncated protein. On the basis of shared ethnicity and haplotype analysis, Kelsell et al. (2005) concluded that the deletion was a founder mutation in at least 3 of the 4 patients.
In an Italian patient with harlequin ichthyosis (ARCI4B; 242500), Kelsell et al. (2005) identified compound heterozygosity for mutations in the ABCA12 gene: a frameshift mutation in exon 33, 5229delA, and a missense mutation, D2363N (607800.0008) in exon 45 that resulted in reduced protein function.
For discussion of the asp2363-to-asn (D2363N) mutation in the ABCA12 gene that was found in compound heterozygous state in a patient with harlequin ichthyosis (ARCI4B; 242500) by Kelsell et al. (2005), see 607800.0007.
In an African American child with harlequin ichthyosis (ARCI4B; 242500), Kelsell et al. (2005) found a nonsense mutation in ABCA12 gene, arg2203 to ter (R2203X), resulting from a T-to-C substitution in exon 44. The child died at the age of 6 months of septicemia.
In a boy born with harlequin ichthyosis (ARCI4B; 242500), Thomas et al. (2006) identified homozygosity for a gly1179-to-arg (G1179R) substitution in exon 24 of the ABCA12 gene. This residue, in the first transmembrane domain of ABCA12, is conserved in mouse, rat, and chicken orthologs of ABCA12. The unaffected mother was heterozygous for the mutation.
In a Caucasian British girl born with severe ichthyosiform erythroderma (242500), in whom Kelsell et al. (2005) did not identify any mutations by sequencing of the ABCA12 gene, Thomas et al. (2006) used a combination of oligonucleotide arrays, multiplex PCR analysis, and SNP genotyping to identify a heterozygous deletion of exon 8. The exon 8 deletion was inherited from her unaffected mother.
In a female newborn with harlequin ichthyosis (ARCI4B; 242500), Castiglia et al. (2009) identified homozygosity for an 859C-T transition in exon 7 of the ABCA12 gene, resulting in an arg287-to-ter (R287X) substitution. Parental segregation study and microsatellite analysis revealed complete paternal isodisomy. Chorionic villus karyotyping of the fetus had revealed a nonmosaic chromosome 2 trisomy, whereas postnatal peripheral blood karyotype was normal, indicating trisomic rescue.
Consanguineous Italian parents of 3 sibs who had congenital ichthyosis of the lamellar type (ARCI4A; 601277) were identified by El Helou et al. (2022) to be heterozygous for a c.3656C-T transition at a conserved site in exon 25 of the ABCA12 gene, resulting in an ala1219-to-val (A1219V) substitution. The mutation was identified by sequencing of a gene panel consisting of genes underlying congenital ichthyosis and related disorders. The sibs died several decades prior to the identification of the parental mutations, but based on clinical history and parental genetic testing results, El Helou et al. (2022) concluded that the sibs were affected with ARCI4A due to homozygosity for the A1219V mutation in the ABCA12 gene.
Akiyama, M., Sugiyama-Nakagiri, Y., Sakai, K., McMillan, J. R., Goto, M., Arita, K., Tsuji-Abe, Y., Tabata, N., Matsuoka, K., Sasaki, R., Sawamura, D., Shimizu, H. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J. Clin. Invest. 115: 1777-1784, 2005. [PubMed: 16007253] [Full Text: https://doi.org/10.1172/JCI24834]
Akiyama, M. ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. Hum. Mutat. 31: 1090-1096, 2010. [PubMed: 20672373] [Full Text: https://doi.org/10.1002/humu.21326]
Annilo, T., Shulenin, S., Chen, Z. Q., Arnould, I., Prades, C., Lemoine, C., Maintoux-Larois, C., Devaud, C., Dean, M., Denefle, P., Rosier, M. Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34. Cytogenet. Genome Res. 98: 169-176, 2002. [PubMed: 12697999] [Full Text: https://doi.org/10.1159/000069811]
Castiglia, D., Castori, M., Pisaneschi, E., Sommi, M., Covaciu, C., Zambruno, G., Fischer, J., Magnani, C. Trisomic rescue causing reduction to homozygosity for a novel ABCA12 mutation in harlequin ichthyosis. Clin. Genet. 76: 392-397, 2009. [PubMed: 19664001] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01198.x]
El Helou, J., Perry, T. B., Anastasio, N., Holbrook, K. A., Rosenblatt, D. S. Lessons on the value of long term follow-up from genetic counselling of a family with severe autosomal recessive congenital ichthyosis. Molec. Genet. Metab. 135: 309-310, 2022. [PubMed: 35216886] [Full Text: https://doi.org/10.1016/j.ymgme.2022.02.004]
Kelsell, D. P., Norgett, E. E., Unsworth, H., Teh, M.-T., Cullup, T., Mein, C. A., Dopping-Hepenstal, P. J., Dale, B. A., Tadini, G., Fleckman, P., Stephens, K. G., Sybert, V. P., and 15 others. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am. J. Hum. Genet. 76: 794-803, 2005. [PubMed: 15756637] [Full Text: https://doi.org/10.1086/429844]
Lefevre, C., Audebert, S., Jobard, F., Bouadjar, B., Lakhdar, H., Boughdene-Stambouli, O., Blanchet-Bardon, C., Heilig, R., Foglio, M., Weissenbach, J., Lathrop, M., Prud'homme, J.-F., Fischer, J. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum. Molec. Genet. 12: 2369-2378, 2003. [PubMed: 12915478] [Full Text: https://doi.org/10.1093/hmg/ddg235]
Parmentier, L., Clepet, C., Boughdene-Stambouli, O., Lakhdar, H., Blanchet-Bardon, C., Dubertret, L., Wunderle, E., Pulcini, F., Fizames, C., Weissenbach, J. Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus. Europ. J. Hum. Genet. 7: 77-87, 1999. [PubMed: 10094194] [Full Text: https://doi.org/10.1038/sj.ejhg.5200271]
Parmentier, L., Lakhdar, H., Blanchet-Bardon, C., Marchand, S., Dubertret, L., Weissenbach, J. Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-35. Hum. Molec. Genet. 5: 555-559, 1996. Note: Erratum: Hum. Molec. Genet. 5: 862-863, 1996. [PubMed: 8845852] [Full Text: https://doi.org/10.1093/hmg/5.4.555]
Thomas, A. C., Cullup, T., Norgett, E. E., Hill, T., Barton, S., Dale, B. A., Sprecher, E., Sheridan, E., Taylor, A. E., Wilroy, R. S., DeLozier, C., Burrows, N., and 13 others. ABCA12 is the major harlequin ichthyosis gene. J. Invest. Derm. 126: 2408-2413, 2006. [PubMed: 16902423] [Full Text: https://doi.org/10.1038/sj.jid.5700455]