ABCMdb

ABCA12 p.Ser387Asn

Predicted by SNAP2:	A: N (57%), C: D (59%), D: D (63%), E: D (59%), F: D (66%), G: D (63%), H: D (63%), I: D (59%), K: D (53%), L: D (63%), M: N (53%), N: N (82%), P: D (75%), Q: D (53%), R: D (63%), T: N (61%), V: N (57%), W: D (85%), Y: D (71%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, T: N, V: N, W: N, Y: N,

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[hide] The roles of ABCA12 in keratinocyte differentiatio... Dermatoendocrinol. 2011 Apr;3(2):107-12. Epub 2011 Apr 1. Akiyama M
The roles of ABCA12 in keratinocyte differentiation and lipid barrier formation in the epidermis.
Dermatoendocrinol. 2011 Apr;3(2):107-12. Epub 2011 Apr 1., [PMID:21695020]

Abstract [show]
ABCA12 is a member of the large superfamily of ATP-binding cassette (ABC) transporters, which bind and hydrolyze ATP to transport various molecules across limiting membranes or into vesicles. The ABCA subfamily members are thought to be lipid transporters. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids in lamellar granules to the apical surface of granular layer keratinocytes. Extracellular lipids, including ceramide, are thought to be essential for skin barrier function. ABCA12 mutations are known to underlie the three main types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations lead to defective lipid transport via lamellar granules in the keratinocytes, resulting in malformation of the epidermal lipid barrier and ichthyosis phenotypes. Studies of ABCA12-deficient model mice indicate that lipid transport by ABCA12 is also indispensable for intact differentiation of keratinocytes.

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36 One patient was homozygous for the splice site mutation c.3295-2A>G4 and another was compound heterozygous for p.Ser387Asn and p.Thr1387del.29 Only one heterozygous mutation, p.Ile1494Thr, was identified in the other patient.30 Cultured keratinocytes from all three patients showed apparently disturbed glucosylceramide transport, although this assay is not quantitative. Login to comment
37 One patient was homozygous for the splice site mutation c.3295-2A>G4 and another was compound heterozygous for p.Ser387Asn and p.Thr1387del.29 Only one heterozygous mutation, p.Ile1494Thr, was identified in the other patient.30 Cultured keratinocytes from all three patients showed apparently disturbed glucosylceramide transport, although this assay is not quantitative. Login to comment

[hide] ABCA12 mutations and autosomal recessive congenita... Hum Mutat. 2010 Oct;31(10):1090-6. Akiyama M
ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts.
Hum Mutat. 2010 Oct;31(10):1090-6., [PMID:20672373]

Abstract [show]
Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATP-binding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

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106 One patient was a homozygote for a splice site mutation c.3295À2A4G [Akiyama et al., 2005] and another patient was a compound heterozygote for p.Ser387Asn and p.Thr1387del [Akiyama et al., 2006a]. Login to comment

[hide] Expression of the keratinocyte lipid transporter A... Am J Pathol. 2007 Jul;171(1):43-52. Yamanaka Y, Akiyama M, Sugiyama-Nakagiri Y, Sakai K, Goto M, McMillan JR, Ota M, Sawamura D, Shimizu H
Expression of the keratinocyte lipid transporter ABCA12 in developing and reconstituted human epidermis.
Am J Pathol. 2007 Jul;171(1):43-52., [PMID:17591952]

Abstract [show]
Serious defects in the epidermal keratinocyte lipid transporter ABCA12 are known to result in a deficient skin lipid barrier, leading to harlequin ichthyosis (HI). HI is the most severe inherited keratinizing disorder and is frequently fatal in the perinatal period. To clarify the role of ABCA12, ABCA12 expression was studied in developing human skin and HI lesions artificially reconstituted in immunodeficient mice. By immunofluorescent study, ABCA12 was expressed in the periderm of the early stage two-layered human fetal epidermis. After formation of a three-layered epidermis, ABCA12 staining was seen throughout the entire epidermis. ABCA12 mRNA expression significantly increased during human skin development and reached 62% of the expression in normal adult skin, whereas the expression rate of transglutaminase 1, loricrin, and kallikrein 7 remained low. We transplanted keratinocytes from patients with HI and succeeded in reconstituting HI skin lesions in immunodeficient mice. The reconstituted lesions showed similar changes to those of patients with HI. Our findings demonstrate that ABCA12 is highly expressed in fetal skin and suggest that ABCA12 may play an essential role under both the wet and dry conditions, including the dramatic turning point from a wet environment of the amniotic fluid to a dry environment after birth.

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51 One patient harbored a homozygous splice site mutation c.3295-2AϾG and the other harbored heterozygous mutations: p.Ser387Asn and c.4158_4160del (p.Thr1387del) as previously reported.36 In detail, patients` keratinocytes were isolated from lesional epidermis after separation from the dermis by overnight treatment of dispase I (Godoshusei, Chiba, Japan). Login to comment
61 Thus, with the same methods, we reconstituted HI lesions using keratinocytes from another patient with HI who had heterozygous mutations affecting both ABCA12 alleles, p.Ser387Asn and c.4158_4160del (p.Thr1387del) (see Ref. 37 for further detailed analysis of the reconstituted lesions). Login to comment
128 We regenerated HI skin lesions using cultured keratinocytes harboring ABCA12 mutations p.Ser387Asn and c.4158_4160del (p.Thr1387del) and normal human fibroblasts. Login to comment
60 Thus, with the same methods, we reconstituted HI lesions using keratinocytes from another patient with HI who had heterozygous mutations affecting both ABCA12 alleles, p.Ser387Asn and c.4158_4160del (p.Thr1387del) (see Ref. 37 for further detailed analysis of the reconstituted lesions). Login to comment
127 We regenerated HI skin lesions using cultured keratinocytes harboring ABCA12 mutations p.Ser387Asn and c.4158_4160del (p.Thr1387del) and normal human fibroblasts. Login to comment

[hide] Compound heterozygous mutations including a de nov... J Invest Dermatol. 2006 Jul;126(7):1518-23. Epub 2006 May 4. Akiyama M, Sakai K, Sugiyama-Nakagiri Y, Yamanaka Y, McMillan JR, Sawamura D, Niizeki H, Miyagawa S, Shimizu H
Compound heterozygous mutations including a de novo missense mutation in ABCA12 led to a case of harlequin ichthyosis with moderate clinical severity.
J Invest Dermatol. 2006 Jul;126(7):1518-23. Epub 2006 May 4., [PMID:16675967]

Abstract [show]
Harlequin ichthyosis (HI) is one of the most devastating genodermatoses. Recently, ABCA12 mutations were identified as the cause of HI. A newborn Japanese male demonstrated the typical features of HI. The patient was treated with oral etretinate and his general condition has been good (now aged 1.5 years). This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A (S387N) in exon 10 and a maternal deletion mutation 4158_4160delTAC (T1387del) in exon 28 of ABCA12. T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5' triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein. Conversely, the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12. Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells. Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient. No de novo mutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis. The present case suggested that a de novo ABCA12 mutation might underlie HI.

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4 This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G4A (S387N) in exon 10 and a maternal deletion mutation 4158_4160delTAC (T1387del) in exon 28 of ABCA12. Login to comment
6 Conversely, the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12. Login to comment
16 In the study of this case, we have found a compound heterozygous ABCA12 combination of mutations, a novel de novo missense mutation, S387N, in exon 10 and a maternal deletion mutation T1387del in exon 28 in a newborn HI baby. Login to comment
20 In addition, the novel mutation S387N was the first reported de novo mutation in ABCA12. Login to comment
33 The mutation 1160G4A transition was a novel missense mutation that changed a serine residue of codon 387 to an asparagine residue (S387N). Login to comment
34 This missense mutation S387N was not found in either in the parent`s (father or mother), although the patient`s mother was heterozygous for the deletion mutation 4158_4160delTAC (Figure 2). Login to comment
35 Thus, the missense mutation S387N was thought to be a de novo mutation and the deletion mutation was a maternal mutation. Login to comment
52 1160G>A (S387N) 4158_4160delTAC (T1387del) (maternal) a b Patient Control Patient Control Father Mother Father Mother A A A A A A A A A A AA A A A A AA AA A A A A A A A A AA A A A AC C C C C C C CC C C CC C C CCC C C CC C C C CCCT T TTN N N N N N N N N T TTT T T TT T T T T T TT T T T T TTT G GGGGGGGGGGG GG GG G GG G G G G (de novo) TAC TAC Figure 2. Login to comment
54 (a) Direct sequencing revealed a heterozygous 1160G4A transition (a missense mutation S387N) in exon 10 of ABCA12 of the patient, but not in his parents or normal control samples. Login to comment
96 The novel de novo mutation S387N in the present patient is located outside all of the known ABCA12 active transporter sites, within the cytoplasmic domain at N-terminus of ABCA12 polypeptide (Figure 6). Login to comment
98 Thus, one would predict the de novo missense mutation S387N not to lead to a serious ABCA12 functional loss. Login to comment
111 The present novel missense mutation S387N in our case was the first de novo mutation reported in ABCA12. Login to comment
118 Briefly, genomic DNA isolated from peripheral blood was subjected to PCR amplification, followed by direct automated NH2 (de novo) (Maternal) T1387del (exon 28) S387N (exon 10) Cytoplasmicside B A COOH ATP-binding cassettes A B Walker A and B motifs Active transport signature Membrane Figure 6. Login to comment
121 Note that the de novo missense mutation S387N is located in the intracytoplasmic region between the N-terminus and the first transmembrane domain, not in any active sites, and the other, deletion mutation T1387del is within the first ATP-binding cassette, which is thought to be important for ABCA12 lipid transporter activity. Login to comment

[hide] The roles of ABCA12 in epidermal lipid barrier for... Biochim Biophys Acta. 2014 Mar;1841(3):435-40. doi: 10.1016/j.bbalip.2013.08.009. Epub 2013 Aug 15. Akiyama M
The roles of ABCA12 in epidermal lipid barrier formation and keratinocyte differentiation.
Biochim Biophys Acta. 2014 Mar;1841(3):435-40. doi: 10.1016/j.bbalip.2013.08.009. Epub 2013 Aug 15., [PMID:23954554]

Abstract [show]
ATP-binding cassette (ABC) transporters form a large superfamily of transporters that bind and hydrolyze ATP to transport various molecules across limiting membranes or into vesicles. The ABCA subfamily members are thought to transport lipid materials. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids via lamellar granules. ABCA12 is considered to transport lipids including ceramides to form extracellular lipid layers in the stratum corneum of the epidermis, which is essential for skin barrier function. ABCA12 mutations are known to underlie the three major types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations result in defective lipid transport via lamellar granules in the keratinocytes, leading to ichthyosis phenotypes from malformation of the stratum corneum lipid barrier. Studies on ABCA12-deficient bioengineered models have revealed that lipid transport by ABCA12 is required for keratinocyte differentiation and epidermal morphogenesis. Defective lipid transport due to loss of ABCA12 function leads to the accumulation of intracellular lipids, including glucosylceramides and gangliosides, in the epidermal keratinocytes. The accumulation of gangliosides seems to result in the apoptosis of Abca12(-/-) keratinocytes. It was reported that AKT activation occurs in Abca12(-/-) granular-layer keratinocytes, which suggests that AKT activation serves to prevent the cell death of Abca12(-/-) keratinocytes. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

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83 One patient was homozygous for the splice-site mutation c.3295-2ANG [4], and another was compound heterozygous for p.Ser387Asn and p.Thr1387del [38]. Login to comment