Mutation Database: Mutations of the ATP-binding Cassette Transporter A 12 (ABCA12)

	Mutation Database Mutations of the ATP-binding Cassette Transporter A 12 (ABCA12) associated with harlequin ichthyosis, congenital ichthyosiform erythroderma and lamellar ichthyosis
	This site is maintained and edited by Masashi Akiyama, M.D., Ph.D. and Kaori Sakai, M.S. Department of Dermatology, Nagoya University Graduate School of Medicine Nagoya 466-8550, Japan

Introduction

ABCA12 belongs to a large superfamily of the ATP-binding cassette (ABC) transporters, which aid in the transport of various biomolecules across the limiting membrane. 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 and disturbed keratinocyte differentiation.

Germline mutations in ABCA12 gene (ABCA12) have been described in families with autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). Among ARCI,HI shows apparently the most severe phenotype and approximately a half of the patients die in the neonatal period. CIE is clinically characterized by fine, whitish scales on a background of erythematous skin over the whole body. Patients with LI show large, thick, dark scales over the entire body without serious background erythroderma.

Most mutations in HI are truncation mutations which lead to loss-of-function of ABCA12 peptide, although various kinds of mutations including splice site mutations, missense mutations, small deletions and exon deletions were also reported in HI families. Thus far, it is apparent that complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families harboring ABCA12 mutations, at least one mutation on each allele is to be a missense mutation leading to only one amino acid alteration. Combinations of missense mutations resulting in only one amino acid alteration in the first ATP-binding cassette of the ABCA12 peptide underlie the LI phenotype.

Phenotype	Mutation	Nucleotide change	Exon/intron	Mutation type; outcome	Reference
HI	p.I38HisfsX64	c.107_108insT (gtc att att ttc>gtc att aTt ttt)	2	insertion; truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
HI	p.Ser177GlnfsX26	c.529delT (tca acT tca > tca act cag)	6	small deleltion; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Trp199X	c.596G>A	6	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Gln228X	c.682C>T	6	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Arg287X	c.859C>T	7	nonsense; truncation	Castiglia et al., Clin Genet 2009;76:392-7.
HI	exon deletion (exon8)		8	large deletion; non-truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
CIE	p.Thr345Pro	c.1033A>C	9	missense; non-truncation	Natsuga et al., J Invest Dermatol 2007;127:2669-73.
HI	p.Gln354X	c.1060C>T	9	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Tyr377X	c.1131C>G	10	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Ser387Asn	c.1160G>A	10	missense; non-truncation	Akiyama et al., J Invest Dermatol 2006;126:1518-23.
HI	p.Arg434X	c.1300C>T	12	nonsense; truncation	Akiyama et al., J Clin Invest 2005;115:1777-84.
HI	p.Trp601X	c.1803G>A	15	nonsense; truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
HI	p.Lys674ArgfsX49	c.2021_2022del2 (cta aAA gag>cta aga gat)	16	small deleltion; truncation	Akiyama et al., J Clin Invest 2005;115:1777-84.
HI	p.Ile676PhefsX13	c.2025delG (aaa gaG att>aaa gaa ttc)	16	small deleltion; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Arg714X	c.2140C>T	17	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Leu758PhefsX4	c.2274_2275insT (ttt ttg act>ttt ttT gac)	17	insertion; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Tyr1090X	c.3270delT (gtctaTgagaaa>gtctagagaaa)	23	small deleltion; truncation	Akiyama et al., Br J Dermatol 2006;155:1064-6.
HI	p.Tyr1090X	c.3270T>G	23	nonsense; truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
HI	exon deletion (exon23)		23	large deletion; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	abnormal splicing	c.3295-2A>G (cAg tac atg>cGg tac atg)	intron23	splice site; partial truncation	Akiyama et al., J Clin Invest 2005;115:1777-84.
CIE	p.Gly1136Asp	c.3407G>A	24	missense; non-truncation	Akiyama et al., Br J Dermatol 2008;158:864-7.
HI	p.Gly1179Arg	c.3535G>A	24	missense; non-truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Arg1225X	c.3673C>T	25	nonsense; truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
CIE	p.Trp1235Ser	c.3704G>C	26	missense; non-truncation	Sakai et al., J Invest Dermatol 2009;129:2306-9.
HI	p.Ser1249X	c.3746C>A	26	nonsense; truncation	Akiyama et al., J Invest Dermatol 2007;127:568-73.
HI	unknown	c.3829+1G>A (ttc cca Ggt>ttc cca Agt)	intron26	splice site; unknown	Thomas et al., Br J Dermatol 2008;158:611-3.
HI	p.Trp1294X	c.3882G>A	27	nonsense; truncation	Rajpar et al., Br J Dermatol 2006;155:204-6.
HI	p.Arg1297X	c.3891G>A	27	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
LI	p.Asn1380Ser	c.4139A>G	28	missense; non-truncation	Lefevre et al., Hum Mol Genet 2003;12:2369-78.
LI	p.Gly1381Glu	c.4142G>A	28	missense; non-truncation	Lefevre et al., Hum Mol Genet 2003;12:2369-78.
HI	p.Thr1387del	c.4158_4160del3 (act acT ACc at>act acc at)	28	small deletion; non-truncation	Akiyama et al., J Clin Invest 2005;115:1777-84.
HI	exon deletion (exon 28-53)		28	large deletion; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	p.Gly1421GlufsX39	c.4262delG (atg gGa gtc>atg gag tct)	29	small deleltion; truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
CIE	p.Ile1494Thr	c.4481T>C	30	missense; non-truncation	Natsuga et al., J Invest Dermatol 2007;127:2669-73.
CIE, LI	p.Arg1514His	c.4541G>A	30	missense; non-truncation	Lefevre et al., Hum Mol Genet 2003;12:2369-78.
LI	p.Glu1539Lys	c.4615G>A	31	missense; non-truncation	Lefevre et al., Hum Mol Genet 2003;12:2369-78.
LI	p.Gly1651Ser	c.4951G>A	32	missense; non-truncation	Lefevre et al., Hum Mol Genet 2003;12:2369-78.
CIE	p.Gln1669X	c.5005C>T	33	nonsense; truncation	Akiyama et al., Br J Dermatol 2008;158:864-7.
HI	Asn1671IlefsX4	5012delA (caaaaaaAtagt>caaaaaatagt)	33	small deleltion; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	unknown	c.5125_5128del4 (agaGATGgtatg>agagtatga)	33	small deleltion; truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
HI	p.Trp1744X	c.5231G>A	34	nonsense; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	unknown	c.5381+3_5381+4del2 (tat gcg tAAgtt>tat gcg tgt)	intron34	splice site; unknown	Thomas et al., Br J Dermatol 2008;158:611-3.
CIE	p.Pro1798Leu	c.5393C>T	35	missense; non-truncation	Sakai et al., J Invest Dermatol 2009;129:2306-9.
HI	p.Arg1881X	c.5641C>T	37	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	unknown	c.5690G>C (AAAG gtaa>AAACgtaa)	37	splice site; unknown	Thomas et al., Br J Dermatol 2008;158:611-3.
HI,CIE	p.Arg1950X	c.5848C>T	39	nonsense; truncation	Akiyama et al., J Clin Invest. 2005 Jul;115(7):1777-84.
CIE	p.Thr1980Lys	c.5939C>A	40	missense; non-truncation	Sakai et al., J Invest Dermatol 2009;129:2306-9.
HI	p.Ala2054AspfsX10	c.6160_6161del2 (att GCg att ttc>att gat ttt caa)	42	small deleltion; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	unknown	c.6234G>T (ctg ttt ggG>ctg ttt ggT)	42	splice site; unknown	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	c.Pro2141del	c.6443_6445del3 (ttc cCA Caa ttc>ttc caa ttc)	44	small deletion; non-truncation	Thomas et al., Br J Dermatol 2008;158:611-3.
HI	p.Gln2161X	c.6481C>T	44	nonsense; truncation	Thomas et al., J Invest Dermatol 2006;126:2408-13.
HI	p.Arg2204X	c.6610C>T	44	nonsense; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	p.Asp2365Asn	c.7093G>A	47	missense; non-truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	p.Val2442SerfsX28	c.7322delC (aaa tgt tcC gtc>aaa tgt tcg tcc)	49	small deleltion; truncation	Kelsell et al., Am J Hum Genet 2005;76:794-803.
HI	p.Arg2479Lys	c.7436G>A	50	splice site and missense; partial truncation	Akiyama et al., J Invest Dermatol 2007;127:568-73.
HI,CIE	p.Arg2482X	c.7444C>T	51	nonsense; truncation	Sakai et al., J Invest Dermatol 2009;129:2306-9.

Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence (GenBank NM_173076.2), according to journal guidelines (www.hgvs.org/mutnomen). The initiation codon is codon 1.

References

Akiyama M, Sakai K, Hatamochi A, Yamazaki S, McMillan JR, Shimizu H. 2008.
Novel compound heterozygous nonsense and missense ABCA12 mutations lead to non-bullous congenital ichthyosiform erythroderma.
Br J Dermatol 158:864-867.

Akiyama M, Sakai K, Sato T, McMillan JR, Goto M, Sawamura D, Shimizu H. 2007.
Compound heterozygous ABCA12 mutations including a novel nonsense mutation underlie harlequin ichthyosis.
Dermatology 215:155-159.

Akiyama M, Sakai K, Sugiyama-Nakagiri Y, Yamanaka Y, McMillan JR, Sawamura D, Niizeki H, Miyagawa S, Shimizu H. 2006.
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 126:1518-1523.

Akiyama M, Sakai K, Wolff G, Hausser I, McMillan JR,Sawamura D, Shimizu H. 2006.
A novel ABCA12 mutation 3270delT causes harlequin ichthyosis.
Br J Dermatol 155:1064-1066.

Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, Tsuji-Abe Y, Tabata N, Matsuoka K, Sasaki R, Sawamura D, Shimizu H. 2005.
Mutations in ABCA12 in harlequin ichthyosis and functional rescue by corrective gene transfer.
J Clin Invest 115:1777-1784.

Akiyama M, Titeux M, Sakai K, McMillan JR, Tonasso L, Calvas P, Jossic F, Hovnanian A, Shimizu H. 2007.
DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences.
J Invest Dermatol 127:568-573.

Castiglia D, Castori M, Pisaneschi E, Sommi M, Covaciu C, Zambruno G, Fischer J, Magnani C. 2009.
Trisomic rescue causing reduction to homozygosity for a novel ABCA12 mutation in harlequin ichthyosis.
Clin Genet 76:392-397.

Kelsell DP, Norgett EE, Unsworth H, Teh MT, Cullup T, Mein CA, Dopping-Hepenstal PJ, Dale BA, Tadini G, Fleckman P, Stephens KG, Sybert VP, Mallory SB, North BV, Witt DR, Sprecher E, Taylor AE, Ilchyshyn A, Kennedy CT, Goodyear H, Moss C, Paige D, Harper JI, Young BD, Leigh IM, Eady RA, O'Toole EA. 2005.
Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.
Am J Hum Genet 76:794-803.

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. 2003.
Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2.
Hum Mol Genet12:2369-2378.

Natsuga K, Akiyama M, Kato N, Sakai K, Sugiyama-Nakagiri Y, Nishimura M, Hata H, Abe M, Arita K, Tsuji-Abe Y, Onozuka T, Aoyagi S, Kodama K, Ujiie H, Tomita Y, Shimizu H. 2007.
Novel ABCA12 mutations identified in two cases of non-bullous congenital ichthyosiform erythroderma associated with multiple skin malignant neoplasia.
J Invest Dermatol 127:2669-2673.

Rajpar SF, Cullup T, Kelsell DP, Moss C. 2006.
A novel ABCA12 mutation underlying a case of harlequin ichthyosis.
Br J Dermatol 155:204-206.

Sakai K, Akiyama M, Yanagi T, McMillan JR, Suzuki T, Tsukamoto K, Sugiyama H, Hatano Y, Hayashitani M, Takamori K, Nakashima K, Shimizu H. 2009.
ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma.
J Invest Dermatol 129:2306-2309

Thomas AC, Cullup T, Norgett EE, Hill T, Barton S, Dale BA, Sprecher E, Sheridan E, Taylor AE, Wilroy RS, DeLozier C, Burrows N, Goodyear H, Fleckman P, Stephens KG, Mehta L, Watson RM, Graham R, Wolf R, Slavotinek A, Martin M, Bourn D, Mein CA, O'Toole EA, Kelsell DP. 2006.
ABCA12 is the major harlequin ichthyosis gene.
J Invest Dermatol 126:2408-2413.

Thomas AC, Sinclair C, Mahmud N, Cullup T, Mellerio JE, Harper J, Dale BA, Turc-Carel C, Hohl D, McGrath JA, Vahlquist A, Hellstrom-Pigg M, Ganemo A, Metcalfe K, Mein CA, O'Toole EA, Kelsell DP. 2008.
Novel and recurring ABCA12 mutations associated with harlequin ichthyosis: implications for prenatal diagnosis.
Br J Dermatol 158:611-613.