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Revertant Mosaicism in Ichthyosis with Confetti Caused by a Frameshift Mutation in KRT1

2016; Elsevier BV; Volume: 136; Issue: 10 Linguagem: Inglês

10.1016/j.jid.2016.05.109

1523-1747

Shotaro Suzuki, Toshifumi Nomura, T. Miyauchi, Masae Takeda, Hideki Nakamura, Satoru Shinkuma, Yasuyuki Fujita, Masashi Akiyama, Hiroshi Shimizu,

Wnt/β-catenin signaling in development and cancer

Ichthyosis with confetti (IWC; MIM #609165) is a rare autosomal dominant disorder characterized by widespread ichthyosiform erythroderma and concomitant revertant skin patches resulting from the somatic loss of a disease-causing mutation (Choate et al., 2010Choate K.A. Lu Y. Zhou J. Choi M. Elias P.M. Farhi A. et al.Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.Science. 2010; 330: 94-97Crossref PubMed Scopus (139) Google Scholar). IWC is caused by frameshift mutations in KRT10 (IWC-K10) or KRT1 (IWC-K1) (Choate et al., 2010Choate K.A. Lu Y. Zhou J. Choi M. Elias P.M. Farhi A. et al.Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.Science. 2010; 330: 94-97Crossref PubMed Scopus (139) Google Scholar, Choate et al., 2015Choate K.A. Lu Y. Zhou J. Elias P.M. Zaidi S. Paller A.S. et al.Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.J Clin Invest. 2015; 125: 1703-1707Crossref PubMed Scopus (44) Google Scholar). Because the latter is extremely rare, with only one reported case in the literature, the clinicopathological features of IWC-K1 remain poorly understood. In this study, we analyzed a second family with IWC carrying a KRT1 mutation. The local institutional review board approved this study, and all participants provided written informed consent. In 2008, a 56-year-old Japanese woman was referred with widespread dry, flaky skin that had been present since birth (see Supplementary Figure S1a online). Her son was also affected (see Supplementary Figure S2a online). An initial physical examination showed palmoplantar keratoderma and mild generalized ichthyosis (Figure 1a, and see Supplementary Figure S1a). Moreover, her abdomen and extremities were diffusely erythematous. Skin biopsy results showed hyperkeratosis, parakeratosis, and acanthosis (see Supplementary Figure S1b). Cells with perinuclear vacuolization and two nuclei were also observed in the epidermis. Ultrastructurally, shell-like, electron-lucent areas around the nuclei of keratinocytes were observed (see Supplementary Figure S1c). Mutation analysis identified a heterozygous mutation, c.1758_1759insT (p.Tyr587LeufsTer67) in KRT1 (see Supplementary Figure S1d), previously unreported to our knowledge, in both the proband and her son. This mutation resulted in an erroneous C-terminal extension and an arginine-rich C-terminal domain: the mutant keratin 1 (KRT1) had 15 arginine residues after tyrosine 587, whereas wild-type KRT1 contained only five arginine residues (see Supplementary Figure S3 online). The overexpression of the N-terminal green fluorescent protein-tagged mutant KRT1 in the HaCaT cells resulted in an aberrant accumulation of KRT1 in or around the nucleus (see Supplementary Figure S4 online), suggesting the pathogenicity of the mutation. In 2015, the patient revisited our hospital for the first time since 2008. She exhibited approximately 1,000 normal-appearing spots, up to 15 mm in size, on her extremities (Figure 1b). Looking back at the initial presentation in 2008, we noticed approximately one hundred 1- to 2-mm–sized white spots (Figure 1a). She recognized a few such spots for the first time at age 30 years. Her affected son (who was 34 years old in 2015) also showed 34 normal-appearing spots up to 2 mm in diameter; however, these spots were found only around his popliteal fossae (see Supplementary Figure S2b). Her 7-month-old granddaughter, who was also heterozygous for the mutation, did not present with any white spots, although hyperkeratotic erythema was evident on her extremities (see Supplementary Figure S2c). We performed skin sampling from two of the normal-appearing patches (Figure 2a) and from one of the affected patches of the proband. Notably, the stratum corneum of the normal-appearing patches showed a normal basket-weave pattern without hyperkeratosis, parakeratosis, or acanthosis (Figure 1c). Immunostaining of the affected skin showed aberrant perinuclear localization of KRT1 and reduced protein levels of keratin 2, whereas the normal-appearing skin exhibited normal patterns of these protein signals (Figure 1c). Thus, the white patches were histologically verified as cured. We next determined the KRT1 genotypes of the two white spots using genomic DNA separately extracted from the epidermis and dermis. The mutation was absent in the epidermis of both spots but retained in the dermis (Figure 2b), suggesting that the somatic reversion of the mutation caused the phenotypic recovery. Collectively, we diagnosed the proband with IWC-K1. To elucidate the mechanism that underlies the reversion of the mutation, we performed genome-wide single nucleotide polymorphism (SNP) genotyping, which identified copy-neutral losses of heterozygosity (LOHs) on chromosome arm 12q in only the revertant spots (Figure 2c). These LOHs started from regions centromeric to KRT1 and extended to the telomere of the chromosome. In contrast, no large LOHs were detected elsewhere. These findings show that the reversion of the mutation resulted from mitotic recombination. The affected individuals with IWC-K1 in this study displayed phenotypes distinct from those of IWC-K10. They showed lower intensities of erythema and hyperkeratosis, with a less extensive area of involvement and smaller revertant spots than those of IWC-K10. Moreover, ectropion, ear malformation, mammillae hypoplasia, and short stature, which are all common clinical signs of IWC-K10 (Guerra et al., 2015Guerra L. Diociaiuti A. El Hachem M. Castiglia D. Zambruno G. Ichthyosis with confetti: clinics, molecular genetics and management.Orphanet J Rare Dis. 2015; 10: 115Crossref PubMed Scopus (28) Google Scholar), were not observed in our patients. Our results, together with the first report of IWC-K1 that documented these differences (Choate et al., 2015Choate K.A. Lu Y. Zhou J. Elias P.M. Zaidi S. Paller A.S. et al.Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.J Clin Invest. 2015; 125: 1703-1707Crossref PubMed Scopus (44) Google Scholar), suggest that IWC-causing KRT1 mutations might lead to phenotypes distinct from those of IWC-K10. Although the histology of the first IWC-K1 patient showed prominent coarse keratohyalin granules without parakeratosis (Choate et al., 2015Choate K.A. Lu Y. Zhou J. Elias P.M. Zaidi S. Paller A.S. et al.Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.J Clin Invest. 2015; 125: 1703-1707Crossref PubMed Scopus (44) Google Scholar), our proband exhibited widespread parakeratosis with fewer coarse keratohyalin granules. A mutation analysis of the gene encoding filaggrin (Nomura et al., 2008Nomura T. Akiyama M. Sandilands A. Nemoto-Hasebe I. Sakai K. Nagasaki A. et al.Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan.J Invest Dermatol. 2008; 128: 1436-1441Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar) identified a heterozygous nonsense mutation, c.8666_8667CC>GA, in our proband that likely explains the reduced keratohyalin granules. In the present family, three affected individuals showed a marked difference in their number of revertant spots. Similarly, in the first IWC-K1 family, a 35-year-old proband presented with multiple revertant spots, whereas his three affected offspring aged 3 to 9 years showed no such spots (Choate et al., 2015Choate K.A. Lu Y. Zhou J. Elias P.M. Zaidi S. Paller A.S. et al.Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.J Clin Invest. 2015; 125: 1703-1707Crossref PubMed Scopus (44) Google Scholar). The probands in both the former and latter families noticed normal skin spots for the first time at ages 30 and 22 years, respectively, with the number and size of revertant spots increasing with age. These findings suggest that revertant spots are recognized by patients with IWC-K1 in their twenties or thirties, whereas such spots usually appear by age 3 years in patients with IWC-K10 (Choate et al., 2015Choate K.A. Lu Y. Zhou J. Elias P.M. Zaidi S. Paller A.S. et al.Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.J Clin Invest. 2015; 125: 1703-1707Crossref PubMed Scopus (44) Google Scholar). Remarkably, the number of revertant spots dramatically increased in our proband even after her late fifties. Thus, age might be a key factor for the development of a recognizable size of revertant spots in patients with IWC-K1. Because the reversion of disease-causing mutations is not observed in the epidermolytic ichthyosis (MIM #113800) caused by missense or truncation mutations in KRT1 or KRT10, this study suggests a possible link between C-terminal frameshift mutations in KRT1 or KRT10 and the high frequency of revertant mosaicism in patients with IWC. Elucidating the as yet uncovered molecular basis of revertant mosaicism might pave the way for the development of therapies for this intractable disease. The authors state no conflict of interest. We are indebted to the family members for their participation in this study. This work was supported by a Grant-in-Aid for Scientific Research (C) 15K09738 (to TN) from the Japan Society for the Promotion of Science. Download .pdf (2.74 MB) Help with pdf files Supplementary Data Expanding the Mutation Spectrum of Ichthyosis with ConfettiJournal of Investigative DermatologyVol. 136Issue 10PreviewIchthyosis with confetti is a rare, autosomal dominant disorder caused by frameshift mutations in KRT10 or KRT1 and characterized by the development of white, genetically revertant macules in red, diseased skin. All cases result from mutations affecting the tail domains of keratin-10 or keratin-1, and Suzuki et al. expand the mutation spectrum for ichthyosis with confetti caused by mutations in KRT1, showing that a polyarginine frameshift in the keratin-1 tail can also cause this disorder. Full-Text PDF Open Archive