Akitaka Shibata1, Kazumitsu Sugiura1, Utako Kimura2, Kenji Takamori2 and Masashi Akiyama1*

Departments of Dermatology, 1Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, and 2Juntendo University Urayasu Hospital, Urayasu, Japan. *E-mail: makiyama@med.nagoya-u.ac.jp

Accepted Nov 5, 2012; Epub ahead of print Mar 8, 2013

Hailey-Hailey disease (HHD, MIM 16960) is an autosomal dominant disease characterized by suprabasal cell separation (acantholysis) of the epidermis. The clinical features vary and include crusted erosions with vesicular pustules, and erythematous scaly plaques at sites of friction and flexures. The skin lesions are often exacerbated by heat, sweating, mechanical trauma, infection and exposure in ultraviolet B (UVB) (1). Patients have a defect in ATP2C1 encoding the ATPase, Ca2+-transporting, type 2C, member 1; (ATP2C1) on the Golgi apparatus (2).

We performed mutation analysis of ATP2C1 in a Japanese patient with HHD and identified the heterozygous novel mutation c.212delT (p.Leu71ArgfsX26). This is a very early truncating mutation, which clearly suggests that haploinsufficiency is an underlying patho­mechanism of HHD.

CASE REPORT

A 62-year-old Japanese man showed typical clinical features of HHD, with erythema and painful erosions in his axillae and groin (Fig. 1). He had had these skin symptoms from his late fifties, and they often worsened in summer and improved in winter. Neither the palms nor the nails were involved. He had no apparent family history of any skin disorder. Biopsy specimens from the breast revealed acantholysis and dyskeratosis in the suprabasal layers of the epidermis. From these findings, he was diagnosed with HHD.

Fig. 1. Clinical features of the patient. (a) Demarcated erythema with erosions in the left axilla. (b) Brownish keratotic papules and plaques in the groin.

The ethics committee of Nagoya University approved the studies described below, which were conducted according to the principles of the Declaration of Helsinki. The participant gave written informed consent.

The coding region of ATP2C1 was amplified from genomic DNA by polymerase chain reaction (PCR), as described previously (3). Direct sequencing of the patient’s PCR products revealed the patient to be heterozygous for the previously unreported deletion mutation c.212delT in ATP2C1, resulting in the frameshift p.Leu71ArgfsX26 (Fig. 2).

Fig. 2. Mutational analysis of ATP2C1. (a) Sequence chromatograms of ATP2C1 in the patient show a heterozygous c.212delT allele. (b) Sequence chromatograms of ATP2C1 in a healthy control. (c) Domain structure of ATP2C1 and the mutation site.

DISCUSSION

The phenotypic variations in HHD might be attributable to the interplay of extrinsic and intrinsic factors. The extrinsic factors might include exposure to environmental temperature, amounts of ultraviolet exposure, minor mechanical stimuli from everyday and occupational activities, and environmental pathogens, etc. (4, 5). Modifying the genes might affect ATP2C1 expression level and disease severity in an individual patient.

The identification of a mutation in the ATP2C1 gene as a cause of HHD has important implications in the management of this condition. Based on genetic information, HHD patients might be offered genetic counselling and prenatal diagnosis. To date, more than 100 pathological mutations scattered throughout the ATP2C1 gene have been described; however, no hot spot for causative mutations has been identified. Approximately 20% of these are nonsense mutations, 30% are frame-shift mutations leading to premature termination codons (PTCs) and 28% are missense mutations (6). The fact that 50% of the causative mutations reported to date lead to PTCs suggests that haploinsufficiency is a prevalent mechanism for the dominant inheritance of HHD (7–9) rather than the dominant negative mechanisms that some researchers believe (10).

In the case described here, c.212delT (p.Leu71ArgfsX26) was identified. It is noteworthy that this truncation mutation is in the vicinity of the N-terminus of ATP2C1. In most cases, the protein produced from the mutant allele is absent or markedly reduced as a consequence of nonsense-mediated mRNA decay. Even if the protein were produced from the mutant allele, the protein product would lack most of the ATP2C1 active domains that are typically found on ATPase-Ca2+ pump, and it is thought that the protein would have severely or completely abolished Ca2+ pump function. Thus, it would not be able to cause the dominant negative effect on ATP2C1 function. Haploinsufficiency is considered to be the pathogenetic mechanism of this case. A review of the literature showed an earlier truncating mutation of ATP2C1, c.185_188delATGG, in a patient with HHD (11). The severity of both our case and the patient with the mutation c.185_188delATGG was moderate, and there was no apparent clinical difference between them.

Furthermore, there are 2 reported nonsense mutations c.115C>T and c.163C>T located upstream of our case (3, 12). We think the present patient further supports that haplo­insufficiency, rather than dominant negative effect, of ATP2C1 mutations is the causative mechanism of HHD.

Acknowledgement

This study was supported in part by a Grant-in-Aid for Scientific Research (A) 23249058 (MA) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by “Research on Measures for Intractable Diseases” Project: matching fund subsidy (H23-028) from Ministry of Health, Labour and Welfare of Japan.

The authors declare no conflicts of interest.

REFERENCES