ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa


  • Masashi Akiyama

    Corresponding author
    1. Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
    • Department of Dermatology, Hokkaido University Graduate School of Medicine, North 15 West 7, Sapporo 060-8638, Japan
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    Communicated by Mark H. Paalman


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: 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. Hum Mutat 31:1–7 2010. © 2010 Wiley-Liss, Inc.


Severe autosomal recessive congenital ichthyoses (ARCI) can be devastating to patients' quality of life in those seriously affected, even though other organs are uninvolved. ARCI comprises three major subtypes, harlequin ichthyosis (HI; MIM♯ 242500), congenital ichthyosiform erythroderma (CIE; MIM♯ 242100), and lamellar ichthyosis (LI; MIM♯s 242300, 604777, 601277, 606545) [Akiyama and Shimizu, 2008]. HI is the most devastating congenital ichthyosis, and affected newborns show large, thick, plate-like scales over the whole body with severe ectropion, eclabium, and flattened ears [Akiyama, 2006a]. Patients with CIE demonstrate fine, whitish scales on a background of erythematous skin over the whole body. Conversely, LI is clinically characterized by large, thick, dark scales over the entire body surface without a serious background erythroderma [Akiyama et al., 2003].

Because transglutaminase 1 gene (TGM1; MIM♯ 190195) mutations were identified as the cause in LI in 1995 [Huber et al., 1995; Russell et al., 1995], significant progress has recently been made in the understanding of the molecular basis of the human epidermal keratinization processes, and mutations in several other genes have also been identified in ARCI. In HI cases, only ABCA12 mutations have been reported as underlying genetic defects [Akiyama and Shimizu, 2008]. In contrast, CIE and LI are both heterogeneous genetic disorders and several causative or underlying molecules including ABCA12 have been identified [Jobard et al., 2002; Lefèvre et al., 2003, 2004; Lefèvre, 2006]. Mutations in six genes have been described in non-HI ARCI to date, including TGM1 [Huber et al., 1995; Russell et al., 1995], ABCA12 [Lefèvre et al., 2003; Natsuga et al., 2007], NIPAL4 (also known as ICHTHYIN) [Lefèvre et al., 2004], CYP4F22 [Lefèvre, 2006], ALOX12B and ALOXE3 [Jobard et al., 2002]. Among them, TGM1 is thought to be the most prevalent causative gene [Fischer, 2009; Herman et al., 2009]. TGM1 encodes transglutaminase 1, which is expressed in the upper epidermis and catalyzes crosslinking of cornified cell envelope precursor proteins to form a cornified cell envelope in the stratum corneum [Herman et al., 2009]. NIPAL4 (or ICHTHYIN) encodes a protein of unknown function. ALOX12B and ALOXE3 encode for arachidonate 12(R)-lipoxygenase and arachidonate lipoxygenase-3, respectively. The protein product of CYP4F22, a cytochrome P450 protein, and the two lipoxygenases arachidonate 12(R)-lipoxygenase and arachidonate lipoxygenase-3 are part of the lipid metabolism pathway involved in the formation of ω-hydroxyceramides from arachidonic acid [Brash et al., 2007]. ABCA12 (MIM♯ 607800) missense mutations leading to defects in the ATP-binding cassette were reported in LI cases (type 2 LI [MIM♯ 601277]) [Lefèvre et al., 2003] and ABCA12 truncation mutations were reported underlying HI patients [Akiyama et al., 2005; Kelsell et al., 2005]. Recently, we reported that ABCA12 missense mutations are a major cause of CIE cases in the Japanese population [Akiyama et al., 2008; Natsuga et al., 2007; Sakai et al., 2009]. Thus, ABCA12 mutations lead to all three ARCI clinical phenotypes including HI, LI and CIE and ABCA12 mutations are highlighted as one of the major causes of ARCI.

ABCA12 is a member of the large superfamily of the ATP-binding cassette (ABC) transporters [Annilo et al., 2002], which bind and hydrolyze ATP to transport various molecules across a limiting membrane or into a vesicle [Borst and Elferink, 2002]. The ABCA subfamily members are thought to be lipid transporters [Peelman et al., 2003]. ABCA12 was recognized as a key molecule in keratinocyte lipid transport [Akiyama et al., 2005; Sakai et al., 2007]. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with lipid transport in lamellar granules to the apical surface of granular layer keratinocytes [Akiyama et al., 2005]. In this article, the importance of ABCA12 mutations as a cause for ARCI is reviewed and a genotype/phenotype correlation of ARCI with ABCA12 mutations is discussed.

ABCA12 Mutations

A review of the literature was performed to identify all of the known ABCA12 mutations. To date, 56 ABCA12 mutations have been described (online database: in 66 unrelated families including 48 HI, 10 LI and 8 CIE families (Supp. Table S1 and Fig. 1). 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 ( The initiation codon is codon 1. Mutations have been reported among ARCI patients with African, European, Pakistani/Indian, and Japanese backgrounds, from almost all over the world. Of the 56 mutations, 36% (20) are nonsense, 25% (14) are missense, 20% (11) comprise small deletions, 11% (6) are splice site, 5% (3) are large deletions, and 4% (2) are insertion mutations. At least, 62.5% (35) of the total reported mutations are predicted to result in truncated proteins. There is no apparent mutation hot spot in ABCA12, although mutations underlying LI phenotype are clustered in the region of the first ATP-binding cassette [Lefèvre et al., 2003].

Figure 1.

ABCA12 mutations associated with autosomal recessive congenital ichthyosis. A: Reported ABCA12 mutations and their localization within the ABCA12 cDNA sequence. Mutations in black, red, and blue characters underlie HI, CIE, and LI, respectively. Mutations in green letters lead to two distinct phenotypes, p.Arg1950Ter and p.Arg2482Ter both result in CIE and HI phenotypes; p.Arg1514His underlies both CIE and LI phenotypes. 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 ( The initiation codon is codon 1. B: ABCA12 protein structure and domains. Analysis of the ABCA12 predicted protein disclosed features that are typical of ABCA transporters, and the position of the conserved ATP-binding cassettes as well as that of the two transmembrane domains, each composed of six well-defined hydrophobic helices [Annilo et al., 2002]. See Supp. Table S1 for a complete list of mutations with both DNA and protein names.

The most common reported mutation in ABCA12 is c.7322delC (p.Val2442SerfsTer28) in exon 49, which has been reported in seven HI families with Pakistani background [Kelsell et al., 2005; Thomas et al., 2006, 2008]. This mutation has been identified only in the Pakistani population. Thomas et al. [2008] reported that 80% of HI patients and parents (10 screened) originated from the Pakistani/Indian area had the mutation 7322delC. Microsatellite-based haplotype analysis of the genomic region harboring ABCA12 in three patients homozygous for the mutation c.7322delC suggested that c.7322delC is a possible founder mutation in the Pakistani population [Thomas et al., 2008]. The second most common reported ABCA12 mutation is a missense mutation p.Asn1380Ser in Walker A motif of the first ATP-binding cassette, which is essential for the transporter function of ABCA12 [Lefèvre et al., 2003]. This missense mutation p.Asn1380Ser has been identified in five LI families from Africa (three families from Morocco and two families from Algeria) [Lefèvre et al., 2003]. Haplotype analysis confirmed that p.Asn1380Ser is a founder mutation in the patients from Morocco/Algeria region [Lefèvre et al., 2003]. Out of further 10 different ABCA12 mutations, each mutation has been identified in two unrelated families from certain geographic regions. Among these 10 mutations, 5 ABCA12 mutations, c.2021_2022del2, c.3295 − 2A>G, p.Thr1387del, p.Arg1950Ter, and p.Arg2482Ter, were found in two independent patients from Japan [Akiyama et al., 2005, 2005, 2006a, 2007a; Sakai et al., 2009]. 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 [Lefèvre et al., 2003], Albanian/Bosnian [Thomas et al., 2008], Anglo-Saxon [Thomas et al., 2006], and native American [Kelsell et al., 2005] origins, respectively. These data suggest the presence of founder mutations in patients in Pakistani/Indian, African, European, and Japanese origins.

Clinical Significance; Prevalence of ABCA12 Mutations as a Causative Gene for ARCI Patients

ARCI is a basket diagnosis, and HI, CIE, and LI are the major subtypes comprising the ARCI group. Among the 48 HI families in whom ABCA12 mutation analysis has been reported (Supp. Table S1), ABCA12 mutations have been identified in all HI families; the ABCA12 mutation detection rate is 100% (48/48) in the HI families. Kelsell et al. [2005] reported one HI patient in whom ABCA12 mutation was not detected by direct sequencing analysis. However, multiplex PCR and oligonucleotide array analysis subsequently revealed deletion of exon 8 in this patient [Thomas et al., 2006]. In this context, HI is thought to be genetically homogeneous for causal ABCA12 mutations.

In contrast, CIE and LI, the other two ARCI subtypes, to date, six genes, ABCA12 [Lefèvre et al., 2003], TGM1 [Huber et al., 1995; Russell et al., 1995], ALOX12B (MIM♯ 603741) [Jobard et al., 2002], ALOXE3 (MIM♯ 607206) [Jobard et al., 2002], ICHTHYIN (MIM♯ 609383) [Lefèvre et al., 2004] and FLJ39501 (MIM♯ 611495) [Lefèvre, 2006], have been reported to cause CIE; and four out of these six, ABCA12 [Lefèvre et al., 2003], TGM1 [Huber et al., 1995; Russell et al., 1995], ALOX12B [Jobard et al., 2002], and ICHTHYIN [Lefèvre et al., 2004], are also known to underlie LI. Recently, Fischer [2009] reported that in her cohort of 520 patients from 520 independent families with LI and CIE, causative mutations were detected by direct sequencing analysis in 78% of the patients. Only 5% of the patients were harbored ABCA12 mutations although only exons 28–32 of ABCA12 were sequenced for the majority of the patients in this study [Fischer, 2009]. The results suggest that ABCA12 is rather a minor cause for ARCI probably in the European and African populations, although the exact ethnic background of the 520 families was not provided in the report. Different from the situation in Europe, from the results of our mutation search, ABCA12 mutations were frequently found in CIE families, but not in LI families, at least in the Japanese population [Sakai et al., 2009]. Thus, there might be a difference in the prevalence of causative genes for CIE and LI between the global subpopulations.

Genotype–Phenotype Correlation in ABCA12 Mutations

Several genotype/phenotype correlations with ABCA12 mutations have now come to light.

In HI (Supp. Fig. S1A), 44 ABCA12 mutations were reported to date. Among them, most mutations are truncation mutations including nonsense mutations, frameshift mutations (deletion/insertion mutations), and splice site mutations (Table 1). Other mutations reported in HI families are missense mutations, exon deletions, and single amino acid deletions.

Table 1. Genotype/Phenotype Correlation in ABCA12 Mutations in Harlequin Ichthyosis (HI), Congenital Ichthyosiform Erythroderma (CIE), and Lamellar Ichthyosis (LI)
Genotype →Phenotype
[truncation]+[exon or conserved amino acid deletion]HI
[exon or conserved amino acid deletion]+[exon or conserved amino acid deletion]HI
[truncation]+[missense]HI, CIE
[exon or conserved amino acid deletion]+[missense mutation]HI, CIE
[missense]+[missense]LI, CIE
Phenotype →Genotype
 [truncation]+[exon or conserved amino acid deletion]
 [exon or conserved amino acid deletion]+[exon or conserved amino acid deletion]
 [truncation]+[missense mutation]
 [exon or conserved amino acid deletion]+[missense mutation]
 [missense mutation]+[exon or conserved amino acid deletion]

Most truncation or deletion mutations underlying HI are thought to lead to severe loss of ABCA12 protein function affecting important nucleotide-binding fold domains and/or transmembrane domains. Thus far, in HI patients, at least one mutation on each allele must be a truncation or deletion mutation within a conserved region to cause serious loss of ABCA12 function [Akiyama et al., 2005, 2006a, b, 2007a, b; Castiglia et al., 2009; Kelsell et al., 2005; Rajpar et al., 2006; Thomas et al., 2006, 2008]. Complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in the HI patient phenotype (Table 1).

In contrast, most mutations underlying LI and CIE are missense mutations and are expected to affect ABCA12 function more modestly.

In LI, five ABCA12 mutations were reported in nine families and all the patients were homozygotes or compound heterozygotes for the mutations [Lefèvre et al., 2003]. None of the LI mutations was demonstrated to cause HI phenotype, although one mutation p.Arg1514His was identified to result in both LI and CIE phenotypes (Supp. Table S1). All the five mutations were missense mutations resulting in only one amino acid alteration in the first ATP-binding cassette of the ABCA12 peptide [Lefèvre et al., 2003] (Table 1). All the families were from Africa [Lefèvre et al., 2003]. These LI patients showed clinically generalized LI with large dark pigmented scales, ectropion, palmoplantar keratoderma and no erythema. They were born as collodion babies.

CIE patients (Supp. Fig. S1B) were also reported to harbor ABCA12 mutations as the causative genetic defect [Akiyama et al., 2008; Natsuga et al., 2007; Sakai et al., 2009]. To date, 10 ABCA12 mutations have been reported in eight CIE families. Two mutations, p.Arg1950Ter and p.Arg2482Ter, were identified to cause both CIE and HI disease phenotypes (Supp. Table S1). Only one mutation p.Arg1514His was reported to underlie both CIE and LI phenotypes (Supp. Table S1). In CIE, most underlying mutations are missense mutations. At least one mutation on each allele is a missense mutation in CIE (Table 1). In the CIE cases with ABCA12 mutations, the scales are slightly larger than those in typical CIE cases and are classified as “medium sized” rather than “fine” scales.

Intrafamilial variation, for example, of CIE and HI cases from one family, has never as yet been reported. Thus, there is no evidence that any other gene(s) in these patients play a noticeable role affecting the phenotypes.

Further accumulation of patients and their ABCA12 mutation data is needed to better elucidate genotype/phenotype correlations and will aid in predicting patients' prognosis.

Biological Significance; Pathomechanisms of Ichthyosis Involving ABCA12 Mutations

In HI affected epidermis, several morphologic abnormalities including abnormal lamellar granules in the keratinocyte granular layer and a lack of extracellular lipid lamellae within the stratum corneum had been reported [Akiyama et al., 1994, 1998; Dale et al., 1990; Milner et al., 1992]. Lack of ABCA12 function subsequently leads to disruption of lamellar granule lipid transport in the upper keratinizing epidermal cells resulting in malformation of the intercellular lipid layers of the stratum corneum in HI [Akiyama et al., 2005] (Fig. 2). Cultured epidermal keratinocytes from an HI patient carrying ABCA12 mutations demonstrated defective glucosylceramide transport, and this phenotype was recoverable by in vitro ABCA12 corrective gene transfer [Akiyama et al., 2005]. To date, intracytoplasmic glucosylceramide transport has been studied using cultured keratinocytes from a total of three patients harboring ABCA12 mutations. One patient was a homozygote for a splice site mutation c.3295 − 2A>G [Akiyama et al., 2005] and another patient was a compound heterozygote for p.Ser387Asn and p.Thr1387del [Akiyama et al., 2006a]. Only one heterozygous mutation p.Ile1494Thr was identified in the other patient [Natsuga et al., 2007]. Cultured keratinocytes from all the three patients showed apparently disturbed glucosylceramide transport, although this assay is not quantitative.

Figure 2.

Physiological role(s) of ABCA12 in lipid trafficking of epidermal keratinocytes and the model of ichthyotic pathogenetic mechanisms underlying ABCA12 deficiency. A: Model of how ABCA12 transports lipids for keratinocyte differentiation and epidermal barrier function. ABCA12 in the limiting membrane of lamellar granules transports lipid into the lamellar granules. Accumulated lipid contents in the lamellar granules are secreted to the intercellular space forming the intercellular lipid layers, which are important for epidermal barrier function. B: Model of how loss of ABCA12 function leads to lipid abnormality and lipid barrier malformation in the upper epidermis. Loss-of-function mutations in ABCA12 disrupts lipid accumulation into the lamellar granules and normal lamellar granule formation, resulting in disturbed lipid transport and secretion to the extracellular space and abnormal lipid deposit in the cytoplasm. C: Disruption of epidermal barrier function and epidermal differentiation defects result from malformation of the stratum corneum lipid layers and abnormal intracellular lipid accumulation, respectively. It is hypothesized that lipid barrier defects and disturbed keratinocyte differentiation coordinately cause hyperkeratosis and the ichthyosis phenotype.

Interestingly, ABCA3, a member of the same protein superfamily as ABCA12, functions in pulmonary surfactant lipid secretion again via the production of similar lamellar-type granules within lung alveolar type II cells [Shulenin et al., 2004; Yamano et al., 2001].

In addition, defective lamellar granule formation was observed in the skin of two CIE patients with ABCA12 mutations [Natsuga et al., 2007]. Electron microscopic observation revealed that, in the cytoplasm of granular layer keratinocytes, abnormal, defective lamellar granules were assembled together with some normal-appearing lamellar granules [Natsuga et al., 2007].

Formation of the intercellular lipid layers is essential for epidermal barrier function. In ichthyotic skin with ABCA12 deficiency, defective formation of the lipid layers is thought to result in a serious loss of barrier function and a likely extensive compensatory hyperkeratosis [Akiyama, 2006b].

A study in one Abca12 disrupted Abca12—/— HI model mouse indicated that a lack of desquamation of skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the fivefold thickening of the Abca12—/— stratum corneum using in vivo skin proliferation measurements [Zuo et al., 2008]. It was suggested that this lack of desquamation was associated with a profound reduction in skin linoleic esters of long-chain ω-hydroxyceramides and a corresponding increase in their glucosylceramide precursors. ω-hydroxyceramides are required for correct skin barrier function, and these results from the HI model mice establish that ABCA12 activity is required for the generation of long-chain ceramide esters that are essential for the development of normal skin structure and function [Zuo et al., 2008].

One hypothetical pathomechanism for ABCA12 deficient in ARCI is the differentiation defect theory (Fig. 2), derived from the clinical features of HI patients. Fetuses affected with HI start developing their ichthyotic phenotype while they are in the amniotic fluid where stratum corneum barrier function is not required. Thus, barrier defects cannot be involved directly in the pathogenesis of HI phenotype, at least during the in utero fetal period. In this context, disturbed keratinocyte differentiation is speculated to play an important role in the pathogenesis of HI phenotype. In fact, three dimensional culture studies revealed that HI keratinocytes differentiate poorly using morphologic criteria, and show reduced expression of keratin 1 and defective conversion from profilaggrin to filaggrin [Fleckman et al., 1997].

In an ABCA12 ablated organotypic coculture system, an in vitro model of HI skin, expression of keratinocyte late differentiation-specific molecules was dysregulated [Thomas et al., 2009]. Expression of specific proteases associated with desquamation, kallikrein 5 and cathepsin D, was dramatically reduced in the ABCA12 ablated organotypic coculture system [Thomas et al., 2009]. In the model system, ABCA12 ablation resulted in a premature terminal differentiation phenotype [Thomas et al., 2009]. Furthermore, in the mutant mice carrying a homozygous spontaneous missense mutation, loss of Abca12 function led to premature differentiation of basal keratinocytes [Smyth et al., 2008]. In contrast, in our Abca12/ HI model mice, immunofluorescence and immunoblotting of Abca12/ neonatal epidermis revealed defective profilaggrin/filaggrin conversion and reduced expression of the differentiation-specific molecules, loricrin, kallikrein 5, and transglutaminase 1, although their mRNA expression was upregulated [Yanagi et al., 2010]. These data suggest that ABCA12 deficiency may lead to disturbed keratinocyte differentiation during fetal development, resulting in an ichthyotic phenotype at birth. From these observations, ABCA12 deficiency might have global effects on keratinocyte differentiation, resulting in both impaired terminal differentiation and premature differentiation of the epidermis.

Animal Models

Recently, bioengineered disease models were established to investigate ichthyotic pathomechanisms due to ABCA12 defective function and to aid development of innovative treatments for ichthyosis with ABCA12 deficiency.

We transplanted cultured keratinocytes from patients with HI and succeeded in reconstituting HI skin lesions in immunodeficient mice [Yamanaka et al., 2007]. These reconstructed HI lesions showed similar changes to those observed in HI patients' skin. In addition, we generated Abca12 disrupted (Abca12−/−) mice and our Abca12−/− mice closely reproduced the human HI phenotype, showing marked hyperkeratosis with eclabium and skin fissure [Yanagi et al., 2008a]. Lamellar granule abnormalities and defective ceramide distribution were remarkable in the epidermis. Skin permeability assays of Abca12−/− mouse fetuses revealed severe skin barrier dysfunction after the initiation of keratinization. Surprisingly, Abca12−/− mice also demonstrated lung alveolar collapse immediately after birth. Lamellar bodies in alveolar type II cells from Abca12−/− mice lacked normal lamellar structures [Yanagi et al., 2008a]. The level of surfactant protein B, an essential component of alveolar surfactant, was reduced in the Abca12−/− mice [Yanagi et al., 2008a]. Another group independently developed Abca12−/− mice and the mice also confirmed the clinical features of HI [Zuo et al., 2008]. In addition, a mouse strain carrying a homozygous spontaneous missense mutation was reported to show skin manifestations similar to ichthyosis [Smyth et al., 2008]. Lipid analysis in Abca12 mutant epidermis revealed defects in lipid homeostasis, suggesting that Abca12 plays a crucial role in maintaining lipid balance in the skin [Smyth et al., 2008]. The cells from the Abca12 mutant mouse have severely impaired lipid efflux and intracellular accumulation of neutral lipids [Smyth et al., 2008]. Abca12 was also demonstrated as a mediator of Abca1-regulated cellular cholesterol efflux [Smyth et al., 2008]. Injection of a morpholino designed to target a splice site at the exon 4/intron 4 junction to block Abca12 pre-mRNA processing induced altered skin surface contours, disorganization of the melanophore distribution, pericardial edema and enlargement of the yolk sac at 3 days postfertilization in the larvae of the zebrafish. It was also associated with premature death at around 6 days postfertilization. These results suggest that Abca12 is an essential gene for normal zebrafish skin development and provide novel insight into the function of ABCA12 [reported at the Annual Meeting of the Society for Investigative Dermatology 2010; Abstract, Frank et al. J Invest Dermatol 2010;130:S86].

HI patients often die in the first 1 or 2 weeks of life. However, once they survive beyond the neonatal period, HI survivors' phenotypes improve within several weeks after birth. In order to clarify mechanisms of the phenotype recovery, we studied grafted skin and keratinocytes from Abca12-disrupted (Abca12−/−) mouse [Yanagi et al., 2010]. Abca12−/− skin grafts kept in a dry environment exhibited dramatic improvements in all the abnormalities seen in the model mice. Increased transepidermal water loss, a parameter of barrier defect, was remarkably decreased in grafted Abca12−/− skin. 10 passage-subcultured Abca12−/− keratinocytes showed restoration of intact ceramide distribution, differentiation-specific protein expression, and profilaggrin/filaggrin conversion, which were defective in the primary culture [Yanagi et al., 2010]. These observations suggested that, during maturation, Abca12−/− epidermal keratinocytes regain normal differentiation processes, although the exact mechanisms of this restoration is still unknown [Yanagi et al., 2010].

We tried fetal therapy with systemic administration of retinoid or dexamethasone, which are effective treatments for neonatal HI and neonatal respiratory distress, respectively, to the pregnant mother mice; however, neither improved the skin phenotype or extended the survival period [Yanagi et al., 2008a]. Retinoids were also ineffective in in vivo studies using cultured keratinocytes from the model mice [Yanagi et al., 2010].

Prenatal Diagnosis of Harlequin Ichthyosis

In families with a history of HI, the parents' request for prenatal diagnosis is not easily ignored.

Before the causative gene for HI was identified, prenatal diagnosis had been performed by fetal skin biopsy and electron microscopic observation during the later stages of pregnancies at 19–23 weeks estimated gestational age for more than 20 years [Akiyama et al., 1994, 1999; Blanchet-Bardon et al., 1983; Shimizu et al., 2005]. The late timing of prenatal testing was a heavy burden on the pregnant mothers. In addition, when a fetus was diagnosed as affected, it was a major problem to induce a therapeutic termination at that late stage of pregnancy. After identification of ABCA12 as the causative gene for HI, it has become feasible to perform DNA-based prenatal diagnosis for HI by chorionic villus or amniotic fluid sampling at a much earlier stage of pregnancy, with a significantly lower risk to fetal health and a reduced burden on mothers [Akiyama et al., 2007b]. Indeed, prenatal diagnosis and exclusion of HI by DNA testing were performed in our laboratory [Akiyama et al., 2007b; Yanagi et al., 2008b].

In the near future, it is hoped that much earlier prenatal diagnosis by completely noninvasive analysis of DNA from fetal cells in maternal circulation [Uitto et al., 2003] and preimplantation genetic diagnosis [Fassihi et al., 2006; Wells and Delhantry, 2001] will be available for HI.


I thank the ARCI families for their participation in this research. I also thank Dr. James R. McMillan for his proofreading and comments in the preparation of the manuscript, and Kaori Sakai, M.S., for her technical assistance. Grant sponsor: Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan (to M. Akiyama); grant number: Kiban B 20390304. Grant sponsor: Ministry of Health, Labor and Welfare of Japan (Health and Labor Sciences Research Grants; Research on Intractable Disease; grant number: H22-Nanchi-Ippan-177 (to M. Akiyama). ABCA12 mutation database is available at our site