ABCMdb

ABCA12 p.Gly1651Ser

ClinVar:	c.4951G>A , p.Gly1651Ser D , Pathogenic
Predicted by SNAP2:	A: D (75%), C: D (75%), D: D (91%), E: D (91%), F: D (80%), H: D (85%), I: D (85%), K: D (91%), L: D (85%), M: D (80%), N: D (85%), P: D (91%), Q: D (80%), R: D (91%), S: D (75%), T: D (80%), V: D (85%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Mutations in the transporter ABCA12 are associated... Hum Mol Genet. 2003 Sep 15;12(18):2369-78. Epub 2003 Jul 15. 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 JF, Fischer J
Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2.
Hum Mol Genet. 2003 Sep 15;12(18):2369-78. Epub 2003 Jul 15., [PMID:12915478]

Abstract [show]
Lamellar ichthyosis type 2 (LI2) is a rare autosomal recessive skin disorder for which a gene has been localized on chromosome 2q33-35. We report the identification of five missense mutations in the ABCA12 gene in nine families from Africa affected by LI2. The mutations were homozygous in eight consanguineous families and heterozygous in one non-consanguineous family. Four of these mutations are localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABC proteins. The ABCA12 protein belongs to a superfamily of membrane proteins that translocate a variety of substrates across extra- and intracellular membranes. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3, a lamellar body membrane protein in lung alveolar type II cells, ABCA12 could function in cellular lipid trafficking in keratinocytes.

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No. Sentence Comment
64 Origin of families and mutations Family Number of patients Degree of consanguinity Origin Mutation Effect Exon number A 3 1st Morocco 4142G!A G1381E 28 C 1 1st Morocco 4139A!G N1380S 28 D 1 1st Morocco 4139A!G N1380S 28 E 1 1st Morocco 4139A!G N1380S 28 F 3 1st Algeria 4951G!A G1651S 32 G 3 No Algeria 4139A!G N1380S 28 4851G!A G1651S 32 H 1 1st Mali 4541G!A R1514H 30 I 1 1st Algeria 4139A!G N1380S 28 J 1 1st Algeria 4615G!A E1539K 31 neonate mouse skin (AK028781, AK029031). Login to comment
75 All of the mutations were missense mutations and were found in the region of the protein encoded by exons 28-32: 4139A!G (N1380S) and 4142G!A (G1381E) in exon 28, 4541G!A (R1514H) in exon 30, 4615G!A (E1539K) in exon 31 and 4951G!A (G1651S) in exon 32. Login to comment
78 Two other families from Algeria presented the G1651S mutation (including the family G of the compound heterozygote) and a common haplotype (Fig. 2). Login to comment

[hide] Novel adenosine triphosphate (ATP)-binding cassett... Br J Dermatol. 2012 Jan;166(1):218-21. doi: 10.1111/j.1365-2133.2011.10516.x. Epub 2011 Sep 29. Fukuda S, Hamada T, Ishii N, Sakaguchi S, Sakai K, Akiyama M, Shimizu H, Masuda K, Izu K, Teye K, Tsuruta D, Karashima T, Nakama T, Yasumoto S, Hashimoto T
Novel adenosine triphosphate (ATP)-binding cassette, subfamily A, member 12 (ABCA12) mutations associated with congenital ichthyosiform erythroderma.
Br J Dermatol. 2012 Jan;166(1):218-21. doi: 10.1111/j.1365-2133.2011.10516.x. Epub 2011 Sep 29., [PMID:21729033]

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29 Patient 4 had compound heterozygosity Table 1 Summary of mutation analysis of ABCA12 in the present study Patient Age, sex Mutation Maternal Paternal 1 3 years, girl Compound heterozygous p.Thr1575Pro (c.4723A>C) c.6031delG 2 9 years, girl Compound heterozygous p.Arg986Trp (c.2956C>T) c.5940-1G>C 3 4 months, boy Compound heterozygous p.Asn1380Ser (c.4139A>G) c.5128+3A>G 4 3 months, boy Compound heterozygous p.Thr1575Pro (c.4723A>C) p.Gly1651Ser (c.4951G>A) (a) (b) (c) (d) (e) Fig 1. Login to comment
35 Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2012 166, pp212-235 Correspondence of missense mutations [(p.Thr1575Pro)+(p.Gly1651Ser)]. Login to comment
38 Two recurrent mutations (p.Asn1380Ser and p.Gly1651Ser) have been reported previously in LI2.6 These mutations were not found in 200 normal, unrelated Japanese alleles. Login to comment
66 Patient 1 with severer features had a heterozygous truncation mutation (c.6031delG) on another allele, while patient 4, with a milder phenotype, had another heterozygous missense mutation (p.Gly1651Ser). 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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55 As for the other five mutations, p.Trp1294Ter, p.Gly1651Ser, p.Tyr1090Ter, c.2025delG, and p.Trp1744Ter were found in two independent families with Pakistani [Rajpar et al., 2006; Thomas et al., 2006], Algeria [Lefe`vre et al., 2003], Albanian/ Bosnian [Thomas et al., 2008], Anglo-Saxon [Thomas et al., 2006], and native American [Kelsell et al., 2005] origins, respectively. Login to comment

[hide] Novel ABCA12 missense mutation p.Phe2144Ser underl... J Dermatol. 2013 Jul;40(7):581-2. doi: 10.1111/1346-8138.12169. Epub 2013 May 19. Shimizu Y, Sugiura K, Aoyama Y, Ogawa Y, Hitomi K, Iwatsuki K, Akiyama M
Novel ABCA12 missense mutation p.Phe2144Ser underlies congenital ichthyosiform erythroderma.
J Dermatol. 2013 Jul;40(7):581-2. doi: 10.1111/1346-8138.12169. Epub 2013 May 19., [PMID:23682801]

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No. Sentence Comment
14 The homozygous mutation p.Asn1380Ser and the compound heterozygous mutations p.Asn1380Ser and p.Gly1651Ser were previously reported to underlie typical LI phenotypes.3 In this regard, we hypothesized that the difference between p.Asn1380Ser/p.Gly1651Ser and p.Phe2144Ser may determine whether the phenotype is LI or CIE. Login to comment
27 The homozygous mutation p.Asn1380Ser and the compound heterozygous mutations p.Asn1380Ser and p.Gly1651Ser underlie lamellar ichthyosis (LI). Login to comment