Conflicts of interest: None.
A novel mutation of keratin 17 gene in a pedigree with pachyonychia congenita type 2
Article first published online: 26 DEC 2012
© 2013 The International Society of Dermatology
International Journal of Dermatology
Volume 52, Issue 1, pages 117–119, January 2013
How to Cite
Qiang, W., Kaibo, W., Tienan, L., Guilan, Z., Yueyang, L., Ting, X. and Fangji, S. (2013), A novel mutation of keratin 17 gene in a pedigree with pachyonychia congenita type 2. International Journal of Dermatology, 52: 117–119. doi: 10.1111/j.1365-4632.2010.04667.x
- Issue published online: 26 DEC 2012
- Article first published online: 26 DEC 2012
Pachyonychia congenita (PC) is a group of autosomal dominant skin disorders characterized by hypertrophic nail dystrophy. There are two main clinical subtypes of PC: type 1 (PC-1) (Jadassohn–Lewandowsky syndrome), and type 2 (PC-2) (Jackson–Lawler syndrome). PC-2 is readily differentiated from PC-1 by multiple steatocysts and/or natal teeth and is caused by mutations in keratin 17 or keratin 6b.
Here, we report a novel mutation in a Chinese pedigree of PC-2 with typical clinical presentations and an autosomal dominant inheritance pattern (Fig. 1).
The proband was a 30-year-old man, who had been born with natal teeth and who had developed thickened toenails and fingernails of a yellow–grayish color by the age of one year. He had suffered recurrent blistering on the feet after long periods of walking, followed by gradual thickening of the plantar keratoderma. Multiple pilosebaceous cysts presented all over his body at puberty. No hair abnormality was observed. Skin biopsy from the proband’s cyst revealed the histopathological characteristics typical of steatocysts (Fig. 2d).
All affected individuals in this family had nail dystrophy (Fig. 2a), plantar keratoderma (Fig. 2b), and teeth at birth, and adult patients had multiple steatocystomas (Fig. 2c). These characteristics satisfy the key diagnostic features of PC-2.
After obtaining informed consents, 2 ml peripheral blood was obtained from each of the available family members and from 100 unrelated controls. Genomic DNA was extracted using a blood DNA extraction kit (Tiangen Biotech Co., Beijing, China). We excluded the possibility of mutations in exon 1 of keratin 17 (K17) and keratin 6b, the most likely regions for mutations, by DNA sequencing. A 400-bp nucleotide covering exon 6 of K17 was amplified using the sense primer 5′-CAGAAGAGGGCATTGACCAT-3′ and the antisense primer 5′-CCCCAGGGCCGAAGCCACGC-3′. Polymerase chain reactions (PCRs) were amplified using the following program: 15 minutes at 94 °C; 35 cycles of one minute at 94 °C, one minute at 58 °C, and one minute at 72 °C; and a final extension five minutes at 72 °C (as described by Smith et al.). 1
Direct sequencing of genomic PCR products revealed a heterozygous missense mutation c.1163 T > G in exon 6 of K17 (Fig. 2e). This mutation predicts the amino acid change leucine to arginine (p.L388R) in the highly conserved helix termination motif of K17. The mutation was carried by the other affected subjects but was not found in the unaffected and unrelated control individuals.
Keratins are heterodimeric proteins that form the intermediate filament cytoskeleton of the epidermis.2 Keratins share a common structure with other intermediate filament proteins, a central alpha-helical rod domain, which is important for polymerization. The rod domain is subdivided into four helical segments, 1A, 1B, 2A, and 2B, by three flexible non-helical linker domains, L1, L12, and L2. In the regions, the sequences at the beginning of helix 1A, termed the “helix initiation motif”, and at the end of helix 2B, termed the “helix termination motif”, are highly conserved and are the most critical for the assembly of the intermediate filaments in vivo and in vitro.3–5
With no exception, all K17 mutations reported are within the highly conserved helix boundary motif regions at either end of the keratin rod domain.6 These sequences of about 20 amino acids contain remarkable evolutionary sequence conservation and are thought to mediate end-to-end interactions in keratin assembly.7 Most of the known mutations were located at the 1A domain of K17 gene. Only two mutations, including that in the current report (c.1163 T > G), have been reported in the 2B domain. The other mutation in the 2B domain, c.1163 T > C at the same position (p.L388P), was described prior to our report.1 Interestingly, the phenotypes of the two mutations included nail dystrophy, plantar keratoderma, and pilosebaceous cysts; moreover, both subjects had been born with natal teeth. On this basis, we speculate that this position is critical to the assembly of the keratins.
- 2Disorders of keratinization: from rare to common genetic disease of skin and other epithelial tissues. Ulster Med J2007; 76: 72–82., .
- 3Genereviews: Pachyonichia Congenital. Seattle, WA: Gene Tests University of Washington. http://www.genetests.org. [Accessed March 20, 2010]., , , et al.