Kazumitsu Sugiura and Masashi Akiyama*
Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. *E-mail: email@example.com
Accepted Nov 24, 2014; Epub ahead of print Nov 26, 2014
Autosomal recessive congenital ichthyosis (ARCI) includes a wide range of ichthyosis phenotypes, including harlequin ichthyosis, lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), and self-improving collodion ichthyosis (SICI) (1, 2). To date, 9 causative genes for ARCI have been identified (1, 2). ALOXE3 is a causative gene in LI as well as CIE, and it encodes the eLOX-3 lipoxygenase, which is predominantly synthesised in the epidermis. ARCI caused by an ALOXE3 mutation is very rare, with less than 30 families with the mutation reported in the literature. The previously reported cases with homozygous or compound heterozygous ALOXE3 mutations were from Europe, North Africa, the Middle East, and South Asia (3–8). Here, we describe an LI patient with a previously unreported homozygous ALOXE3 mutation in a consanguineous family from Japan and review ARCI cases with ALOXE3 mutations.
The patient is a 58-year-old Japanese woman who presented with symptoms of ichthyosis since birth. Her parents were first cousins. She has 3 siblings, of which one has a similar ichthyosis phenotype (Fig. 1a). Ectropion was not reported at birth. She showed brown-to-gray scaling without erythroderma on her trunk and extremities (Fig. 1b). She did not show palmar keratosis or alopecia, but did show mild plantar keratosis during middle age (Fig. 1c, d).
Fig. 1. Pedigree, clinical features, and ALOXE3 sequence data of the patient; sequence alignments around the missense mutation; and a summary of known ALOXE3 mutations. (a) Pedigree of the patient. (b) The patient showed brown-to-gray scaling bilaterally on the lower legs. (c) The patient did not show palmar keratosis. (d) The patient showed mild plantar hyperkeratosis. (e) Sequence data of ALOXE3 in the patient with the mutation and a control without the mutation. The arrow indicates c.992T>C (homozygous). (f) The eLOX-3 protein domain structure and ALOXE3 mutations from this study and the literature. The previously unreported missense mutation identified in this study, p.Leu331Pro, is shown in red. A blue box and a green box indicate the N-terminal β-barrel LH2 domain and an inserted specific extra domain, respectively. Pink boxes indicate C-terminal catalytic lipoxygenase domain from amino acid position 126. Putative iron ligands of the active sites are in red.
Following ethical approval, informed written consent was obtained in compliance with the Declaration of Helsinki guidelines. The coding regions, including the exon-intron boundaries of TGM1, ABCA12, ALOX12B, and ALOXE3, were amplified from genomic DNA by PCR as described elsewhere (3). Direct sequencing of the patient’s PCR products revealed that the patient had a homozygous ALOXE3 mutation, c.992T>C (p.Leu331Pro) (gene accession number: NM_021628.2) (Fig. 1e). p.Leu331Pro was analysed using SIFT (http://sift.jcvi.org/) and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/). The SIFT score was 0.000 and PolyPhen-2 score was 1.000; both scores predicted that p.Leu331Pro had damaging effects. We found no mutation in the other 3 genes tested. c.992T>C was not detected in the 200 control alleles (100 control individuals, data not shown). Thus, the patient was diagnosed as having LI caused by the homozygous ALOXE3 mutation.
All previously reported ARCI cases with ALOXE3 mutations have been in families from Europe, North Africa, the Middle East, and South Asia (Fig. 1f, Table SI1). To our knowledge, the present patient is the first case with ALOXE3 mutations in a family from East Asia. Our case suggests that ALOXE3 mutations are possibly found in families worldwide. We reported more than 50 Japanese cases of ARCI that had TGM1, ABCA12, ALOX12B, or CYP4F22 mutations (2, 9, 10). Although we do not have data indicating how often patients with ichthyosis are offered genetic testing in Japan, no other patients with ALOXE3 mutations have been found to date. We hypothesise that the carrier rate of ichthyosis-causing ALOXE3 mutations may be very low in Japan.
We reviewed 39 cases of ARCI from 29 families that had ALOXE3 mutations, including the case described here (3–8) (Table SI1). Thirteen ALOXE3 mutations have been reported (Fig. 1f). Truncation mutations, missense mutations, and an in-frame small deletion/insertion mutation have been reported. The truncation mutations include nonsense mutations, a deletion mutation resulting in a frame shift, and a splice site mutation. In 2 cases, ALOXE3 mutations were identified only in one allele. In the literature (Table SI1), ARCI phenotypes caused by ALOXE3 mutations were categorised as CIE, LI, and SICI. In 3 cases, clinical features were not described, and their ARCI phenotypes were unknown.
In conclusion, the present case clearly indicates that ALOXE3 is a possible causative gene in East Asian ARCI patients.
The authors thank Ms. Haruka Ozeki and Ms. Yuka Terashita for their technical help in analysing TGM1, ABCA12, ALOX12B, and ALOXE3 mutations. This study was supported in part by Grant-in-Aid for Scientific Research (A) 23249058 (to M.A.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the “Research on Measures for Intractable Diseases” Project: Matching Fund Subsidy (H23-028) from the Ministry of Health, Labour, and Welfare of Japan.
The authors declare no conflicts of interest.