A missense mutation in exon 1 of the keratin 9 gene in a Japanese patient with “Vörner type” hereditary palmoplantar keratoderma

ARTICLE

Auteur(s) : Jun-Ichi Sakabe, Motonobu Nakamura, Yoshiki Tokura

Department of Dermatology, University of Occupational and Environmental Health (UOEH), 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan

Epidermolytic hereditary palmoplantar keratoderma (EHPPK; OMIM: 144200) or Vörner type PPK is characterized by hyperkeratotic lesions confined to the palms and soles, histological granular degeneration and mutations in keratin 9 gene (KRT9; NCBI: NM000226) [1-5]. Here, we report a Japanese patient with EHPPK showing a missense mutation (R162Q) in KRT9 located in the 1A rod domain, the highly conserved helix initiation motif of keratin 9.

A 28-year-old Japanese man was referred to us for evaluation of palmar and plantar hyperkeratotic lesions. The condition had developed within the first year of life and progressed until 20 years of age. He sometimes shaved the hyperkeratotic surface of the soles, but the cornified lesion recovered within a few weeks. On examination, there was a markedly thick cornified layer on the soles and palms (figures 1A,B). The dorsal aspects of the hands and feet were not affected, and the borderline between the lesional and normal skin was clear. Hyperhidrosis was unremarkable. The patient was otherwise healthy. His one-year-old daughter had the same hyperkeratotic lesions on the bilateral palms and soles, but to a lesser degree. The family history was otherwise negative for similar disorders as his parents had no palmoplantar hyperkeratosis.

A skin biopsy specimen was taken from the inner aspect of his right foot. There was epidermolytic hyperkeratosis exhibiting coarse keratohyaline granules and granular degeneration (figure 1C). Thus, we diagnosed the patient as having EHPPK.

Genomic DNA was extracted from peripheral blood leukocytes. As previously reported [6], the genomic regions of the KRT9 gene exon1 were amplified via polymerase chain reaction (PCR), using a forward : K9.E1F : 5’-GGAGGTGACTCTGCTCTTGG-3’ and a reverse: K9.E1R : 5’-AGGTGGATTCCCTGGCTATT-3’ primer pair. A direct sequencing analysis identified a G to A transversion at nucleotide (nt) position 551, resulting in the substitution of glutamine (Q) for arginine (R), in the patient, as compared with the normal sequence (figure 1D).

The R162Q missense mutation identified in our case was not novel, since the mutation was located within codon R162, in which the most common mutations, R162W and R162P, have been reported. However this is the second report of the R162Q missense mutation in Japanese patients with EHPPK. This mutation has frequently been seen in non-Japanese patients, as approximately 20% Western cases had this mutation [1-3]. The result confirms the previous reports of KRT9 mutation underlying EHPPK and re-emphasizes the importance of codon R162 for maintenance of the intermediate keratin filament network. Since keratin 9 is confirmed to the volar skin, the abnormality of keratin 9 induces palmoplantar lesions. This dominant-negative effect on keratin network formation led to the disruption of keratin filament formation, and development of epidermolytic hyperkeratosis [4].

Acknowledgments

Références

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4 Kobayashi S, Tanaka T, Matsuyoshi N, et al. Keratin 9 point mutation in the pedigree of epidermolytic hereditary palmoplantar keratoderma perturbs keratin intermediate filament network formation. FEBS Lett 1996; 386: 149-55.

5 Feng W, Han W, Man X, et al. Identification of the keratin 9 KRT9) N161S mutation in a Chinese kindred with epidermolytic palmoplantar keratoderma. Eur J Dermatol 2008; 18: 387-90.

6 Kabashima K, Sakabe J, Yamada Y, et al. “Nagashima-Type” Keratosis as a Novel Entity in the Palmoplantar Kertoderma category. Arch Dermatol 2008; 144: 375-9.