Naegeli-Franceschetti-Jadassohn Syndrome and Dermatopathia Pigmentosa Reticularis: Two Allelic Ectodermal Dysplasias Caused by Dominant Mutations in KRT14
2006; Elsevier BV; Volume: 79; Issue: 4 Linguagem: Inglês
10.1086/507792
ISSN1537-6605
AutoresJennie Lugassy, Peter Itin, Akemi Ishida‐Yamamoto, Kristen E. Holland, Susan Huson, Dan Geiger, Hans Christian Hennies, Margarita Indelman, Dani Bercovich, Jouni Uitto, Richard N. Bergman, John A. McGrath, Gabriele Richard, Eli Sprecher,
Tópico(s)Genetic and rare skin diseases.
ResumoNaegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central α-helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR. Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central α-helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR. Naegeli-Franceschetti-Jadassohn syndrome (NFJS [MIM 161000]) is a rare autosomal dominant form of ectodermal dysplasia. Among the most distinctive characteristics of this syndrome is the complete absence of dermatoglyphics (fig. 1). Other frequently encountered clinical features include a typical reticulate hyperpigmentation of the skin that tends to slowly disappear with age, palmoplantar keratoderma, and decreased sweating (fig. 1). Enamel defects, other dental anomalies, skin blistering, and nail dystrophy (fig. 1) have been reported in some but not all patients.1Sparrow GP Samman PD Wells RS Hyperpigmentation and hypohidrosis (the Naegeli-Franceschetti-Jadassohn syndrome): report of a family and review of the literature.Clin Exp Dermatol. 1976; 1: 127-140Crossref PubMed Scopus (39) Google Scholar, 2Itin PH Lautenschlager S Meyer R Mevorah B Rufli T Natural history of the Naegeli-Franceschetti-Jadassohn syndrome and further delineation of its clinical manifestations.J Am Acad Dermatol. 1993; 28: 942-950Abstract Full Text PDF PubMed Scopus (52) Google Scholar Dermatopathia pigmentosa peticularis (DPR [MIM 125595]) shares key features with NFJS but has been distinguished from it by lifelong persistence of the skin hyperpigmentation, partial alopecia, and absence of dental anomalies.3Heimer WLD Brauner G James WD Dermatopathia pigmentosa reticularis: a report of a family demonstrating autosomal dominant inheritance.J Am Acad Dermatol. 1992; 26: 298-301Abstract Full Text PDF PubMed Scopus (39) Google Scholar Nevertheless, both disorders have been mapped to a common 6-cM interval on 17q11.2-q21,4Whittock NV Coleman CM McLean WH Ashton GH Acland KM Eady RA McGrath JA The gene for Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21.J Invest Dermatol. 2000; 115: 694-698Crossref PubMed Scopus (16) Google Scholar, 5Sprecher E Itin P Whittock NW McGrath JA Meyer R DiGiovanna JJ Bale SJ Uitto J Richard R Refined mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.J Invest Dermatol. 2002; 119: 692-698Crossref PubMed Scopus (29) Google Scholar supporting the idea that NFJS and DPR are allelic disorders.6Itin PH Lautenschlager S Genodermatosis with reticulate, patchy and mottled pigmentation of the neck—a clue to rare dermatologic disorders.Dermatology. 1998; 197: 281-290Crossref PubMed Scopus (18) Google Scholar To resolve the molecular basis of NFJS and DPR, we studied five families with these disorders. Family 1 is a large multigenerational Swiss family, which was originally described by Naegeli in 1927 and has been followed since then in a number of reports over the past 80 years.2Itin PH Lautenschlager S Meyer R Mevorah B Rufli T Natural history of the Naegeli-Franceschetti-Jadassohn syndrome and further delineation of its clinical manifestations.J Am Acad Dermatol. 1993; 28: 942-950Abstract Full Text PDF PubMed Scopus (52) Google Scholar, 7Naegeli O Chromatophorennavus.Schweiz Med Wochenschr. 1927; 8: 48Google Scholar, 8Franceschetti A Jadassohn W A propos de "l'incontinentia pigmenti," delimitation de deux syndromes differents figurant sous le meme terme.Dermatologica. 1954; 108: 1-28Crossref PubMed Google Scholar Family 2 is from the United States and was first reported with a diagnosis of DPR by Heimer et al.3Heimer WLD Brauner G James WD Dermatopathia pigmentosa reticularis: a report of a family demonstrating autosomal dominant inheritance.J Am Acad Dermatol. 1992; 26: 298-301Abstract Full Text PDF PubMed Scopus (39) Google Scholar Family 3 is living in the United States but originated in England, whereas families 4 and 5 are living in the United Kingdom; patients in these latter three families displayed typical features of NFJS. In addition, diffuse hair loss and absence of dental problems in some patients in family 3 were reminiscent of DPR. Histopathological examination of skin biopsy specimens obtained from patients of family 1 disclosed mild hyperkeratosis of the epidermis, as well as accumulation of upper dermal melanophages and Civatte bodies in areas of hyperpigmentation (data not shown). Biological specimens were obtained with informed and written consent from all participants in accordance with the Helsinki guidelines and after institutional review board approval. We PCR amplified genomic DNA from blood samples, buccal brushings,9Richards B Skoletsky J Shuber AP Balfour R Stern RC Dorkin HL Parad RB Witt D Klinger KW Multiplex PCR amplification from the CFTR gene using DNA prepared from buccal brushes/swabs.Hum Mol Genet. 1993; 2: 159-163Crossref PubMed Scopus (358) Google Scholar or saliva (Oragene [DNA Genotek]) for polymorphic microsatellite markers encompassing the NFJS/DPR interval. PCR products were separated by PAGE and were visualized using the silver-staining method10Merril CR Goldman D Van Keuren ML Gel protein stains: silver stain.Methods Enzymol. 1984; 104: 441-447Crossref PubMed Scopus (278) Google Scholar or an ABI 310 sequencer system, followed by allele sizing with Genescan 3.1 and Genotyper 2.0 software (PE Applied Biosystems). Thirteen members of family 3 were initially genotyped for nine polymorphic microsatellite markers spanning the NFJS/DPR interval previously localized between markers D17S1851 and D17S934 in families 1 and 2.5Sprecher E Itin P Whittock NW McGrath JA Meyer R DiGiovanna JJ Bale SJ Uitto J Richard R Refined mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.J Invest Dermatol. 2002; 119: 692-698Crossref PubMed Scopus (29) Google Scholar Multipoint linkage score analysis of the data generated a maximal LOD score of 2.99 at marker D17S800 for this family, which is suggestive of linkage to the 17q11.2-q21 locus. Two-point linkage analysis of the combined genotyping data for families 1, 2, and 3, calculated across the NFJS/DPR candidate region by use of the SuperLink online software,11Silberstein M Tzemach A Dovgolevsky N Fishelson M Schuster A Geiger D Online system for faster multipoint linkage analysis via parallel execution on thousands of personal computers.Am J Hum Genet. 2006; 78: 922-935Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar generated a LOD score of 6.2 at marker D17S800 with a recombination fraction of 0; multipoint LOD-score analysis performed with the same software package placed the NFJS/DPR locus between markers D17S933 and D17S934, with a maximum LOD score of 8.36 at marker D17S800. Haplotype analysis in family 3 revealed a 14-Mb–long haplotype shared in a heterozygous state by all affected individuals. This region was shown to comprise the critical interval previously identified in families 1 and 25Sprecher E Itin P Whittock NW McGrath JA Meyer R DiGiovanna JJ Bale SJ Uitto J Richard R Refined mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.J Invest Dermatol. 2002; 119: 692-698Crossref PubMed Scopus (29) Google Scholar and therefore did not enable us to further refine the NFJS/DPR locus (fig. 2a). DNA samples from one affected member of family 4 and from a single patient from family 5 were available for genotyping. These two individuals were found to share a common haplotype with family 3 patients between markers D17S946 and D17S2180 (fig. 2a), suggesting that NFJS may be caused in these three families by an identical founder mutation located within a 6-Mb interval flanked by these two markers. Of the 1,266 genes identified on chromosome 17,12Zody MC Garber M Adams DJ Sharpe T Harrow J Lupski JR Nicholson C et al.DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.Nature. 2006; 440: 1045-1049Crossref PubMed Scopus (101) Google Scholar 230 are located within the NFJS/DPR interval. Of particular interest is the presence within this interval of the distal end of a large cluster of genes encoding type I keratin molecules.13Hesse M Zimek A Weber K Magin TM Comprehensive analysis of keratin gene clusters in humans and rodents.Eur J Cell Biol. 2004; 83: 19-26Crossref PubMed Scopus (147) Google Scholar Mutations in 20 different keratin genes have been associated with epithelial genetic disorders, some of which lead to clinical signs of skin blistering, pigmentary changes, or hair and nail abnormalities, all of which can feature, to some extent, in NFJS/DPR.14Irvine AD Inherited defects in keratins.Clin Dermatol. 2005; 23: 6-14Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar In addition, keratin-immunoreactive apoptotic bodies have been described in the dermis of individuals with NFJS.15Frenk E Mevorah B Hohl D The Nageli-Franceschetti-Jadassohn syndrome: a hereditary ectodermal defect leading to colloid-amyloid formation in the dermis.Dermatology. 1993; 187: 169-173Crossref PubMed Scopus (9) Google Scholar According to the NCBI MapViewer, the critical region for NFJS/DPR harbors 12 soft-keratin genes, including KRT10, KRT14, KRT15, KRT16, KRT17, KRT18, KRT19, KRT20, KRT23, and KRT24. Mutations in KRT16 and KRT17 have been associated with pachyonychia congenital (MIM 167200; MIM 167210), a dominant disorder manifesting with palmoplantar keratoderma, nail dystrophy, alopecia, leukokeratosis, pilosebaceous cysts, and acral skin blistering.16Smith FJ Liao H Cassidy AJ Stewart A Hamill KJ Wood P Joval I van Steensel MA Bjorck E Callif-Daley F Pals G Collins P Leachman SA Munro CS McLean WH The genetic basis of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 21-30Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar In contrast, mutations in KRT14 and its expression partner KRT5 are usually associated with dominant or recessive forms of epidermolysis bullosa simplex (EBS [MIM 131900]),17Rugg EL Leigh IM The keratins and their disorders.Am J Med Genet C Semin Med Genet. 2004; 131C: 4-11Crossref PubMed Scopus (41) Google Scholar a mechanobullous disease characterized by prominent skin blistering due to defective formation of the cytoskeleton of basal keratinocytes in the epidermis. Two previous studies4Whittock NV Coleman CM McLean WH Ashton GH Acland KM Eady RA McGrath JA The gene for Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21.J Invest Dermatol. 2000; 115: 694-698Crossref PubMed Scopus (16) Google Scholar, 5Sprecher E Itin P Whittock NW McGrath JA Meyer R DiGiovanna JJ Bale SJ Uitto J Richard R Refined mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.J Invest Dermatol. 2002; 119: 692-698Crossref PubMed Scopus (29) Google Scholar have excluded a pathogenic role for several keratin genes in NFJS/DPR, including KRT15, KRT19, KRT20, and KRT24. Thus, we turned our attention to 15 nonkeratin candidate genes of potential relevance to epithelial differentiation (oligonucleotide sequences and PCR conditions are available on request from the authors): AP1GBP1, AP2B1, ATP6V0A1, and VPS25, encoding proteins involved in vesicle trafficking, which is of importance in the pathogenesis of both pigmentary18Tomita Y Suzuki T Genetics of pigmentary disorders.Am J Med Genet C Semin Med Genet. 2004; 131C: 75-81Crossref PubMed Scopus (119) Google Scholar and cornification19Sprecher E Ishida-Yamamoto A Mizrahi-Koren M Rapaport D Goldsher D Indelman M Topaz O Chefetz I Keren H O'Brien TJ Bercovich D Shalev S Geiger D Bergman R Horowitz M Mandel H A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma.Am J Hum Genet. 2005; 77: 242-251Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar disorders; RAMP2, PERLD1, FZD2, GJA7, GJC1, MMP28, and PPARBP, coding for various elements possibly involved in epithelial differentiation; NKIRAS2, which may regulate NFκB activity, which in turn has been shown to be involved in the pathogenesis of a number of ectodermal dysplasia disorders20Courtois G The NF-κB signaling pathway in human genetic diseases.Cell Mol Life Sci. 2005; 62: 1682-1691Crossref PubMed Scopus (52) Google Scholar; GSDM1 and GSDML, coding for proteins homologous to murine gasdermin 3 which has been shown to play a critical role during hair follicle and sebaceous gland development21Lunny DP Weed E Nolan PM Marquardt A Augustin M Porter RM Mutations in gasdermin 3 cause aberrant differentiation of the hair follicle and sebaceous gland.J Invest Dermatol. 2005; 124: 615-621Crossref PubMed Scopus (57) Google Scholar; and STARD3, involved in transport of lipids, which are required during epidermal differentiation.22Candi E Schmidt R Melino G The cornified envelope: a model of cell death in the skin.Nat Rev Mol Cell Biol. 2005; 6: 328-340Crossref PubMed Scopus (1167) Google Scholar In addition, we reexamined 13 genes previously excluded4Whittock NV Coleman CM McLean WH Ashton GH Acland KM Eady RA McGrath JA The gene for Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21.J Invest Dermatol. 2000; 115: 694-698Crossref PubMed Scopus (16) Google Scholar, 5Sprecher E Itin P Whittock NW McGrath JA Meyer R DiGiovanna JJ Bale SJ Uitto J Richard R Refined mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.J Invest Dermatol. 2002; 119: 692-698Crossref PubMed Scopus (29) Google Scholar: DUSP14, LASP1, GRB7, RARA, MPP2, MPP3, GRN, RABC5, BECN1, ARHN, KRT20, KRT23, and KRT24. This was done because sequence data for these genes have been updated and novel splicing patterns have been identified for many of them. Pathogenic mutations, however, were excluded from the coding sequence of each of these 28 genes. We then assessed keratin genes already known to be associated with phenotypes distinct from NFJS/DPR: KRT14, KRT16, and KRT17. The potential value of reexploring these genes has been highlighted by recent data showing that keratin mutations located at unusual sites can result in unexpected and clinically diverse phenotypes.23Sprecher E Ishida-Yamamoto A Becker OM Marekov L Miller CJ Steinert PM Neldner K Richard G Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 1164: 511-519Crossref Scopus (95) Google Scholar, 24Betz RC Planko L Eigelshoven S Hanneken S Pasternack SM Bussow H Bogaert KV Wenzel J Braun-Falco M Rutten A Rogers MA Ruzicka T Nothen MM Magin TM Kruse R Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease.Am J Hum Genet. 2006; 78: 510-519Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar No mutations were identified in KRT16 and KRT17 but direct sequencing of KRT14 revealed pathogenic mutations in all patients with NFJS/DPR (fig. 2b). In family 1, we identified a single heterozygous guanosine deletion at position 17 (17delG) of the KRT14 cDNA sequence (numbering starting from the initiation codon). This mutation is predicted to result in a frameshift and to generate a stop codon 8 aa downstream of the mutation site, most likely resulting in nonsense-mediated mRNA decay or in the synthesis of a 13-aa unstable peptide. In affected individuals of family 2, we observed a heterozygous C→A transversion at cDNA position 54, resulting in the nonsense mutation C18X. Family 3 patients displayed a heterozygous C→T transition, causing the substitution of a stop codon for a glutamine residue at KRT14 amino acid position 7 (Q7X). As predicted by the genotyping data, the affected individuals of families 4 and 5 were also found to carry this mutation. Sequence analysis of the remainder of the KRT14 coding sequence did not reveal any other pathogenic mutation in any of the affected individuals of families 1–5. However, several heterozygous sequence variants were detected at known polymorphic positions (data not shown), excluding the possibility of a large deletion in one allele of KRT14. To verify the causative mutations, we used two screening approaches. A 343-bp PCR fragment (for 17delG and C18X) or a 202-bp PCR fragment (for Q7X) was amplified using primer pair 5′-GAAAGTGCCAGACCCGCCCCC-3′ and 5′-GCTGAAGCCACCGCCATAG-3′ or primer pair 5′-GAAAGTGCCAGACCCGCCCCC-3′ and 5′-GCCCGCCCCGATGCCGCCCC-3′, respectively. 17delG was verified using denaturing high performance liquid chromatography (dHPLC) heteroduplex analysis as reported elsewhere.19Sprecher E Ishida-Yamamoto A Mizrahi-Koren M Rapaport D Goldsher D Indelman M Topaz O Chefetz I Keren H O'Brien TJ Bercovich D Shalev S Geiger D Bergman R Horowitz M Mandel H A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma.Am J Hum Genet. 2005; 77: 242-251Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar 17delG was absent from a panel of 100 control individuals. To verify the two other mutations, PCR-RFLP assays were used. Mutations C18X and Q7X create a novel recognition site for endonucleases DdeI and BfaI, respectively, which were used for restriction-fragment analysis to confirm the segregation of these mutations with the disease phenotype in families 2 and 3 and to exclude the mutations from a panel of 100 healthy population-matched control individuals. To assess the cellular consequences of the identified KRT14 mutations, we performed ultrastructural analysis of skin biopsy specimens obtained from affected individuals in family 1. Basal epidermal cells displayed condensed keratin filaments (fig. 3b), which is characteristic of aberrant keratin filament assembly25Omary MB Coulombe PA McLean WH Intermediate filament proteins and their associated diseases.N Engl J Med. 2004; 351: 2087-2100Crossref PubMed Scopus (371) Google Scholar and has been observed during the early stages of apoptosis.26van Engeland M Kuijpers HJ Ramaekers FC Reutelingsperger CP Schutte B Plasma membrane alterations and cytoskeletal changes in apoptosis.Exp Cell Res. 1997; 235: 421-430Crossref PubMed Scopus (165) Google Scholar In addition, perinuclear keratin filament retraction was seen in suprabasal cells (fig. 3a). Of note, at the periphery of the suprabasal cells, keratin filaments were normally arranged in elongated bundles and were shown to be attached to inner desmosomal plaques. The most prominent finding was the conspicuous presence of colloid (apoptotic) bodies and amyloid bodies (fig. 3c), as well as melanophages, in the papillary dermis. The present ultrastructural and molecular data indicate that NFJS and DPR are keratin disorders and should be considered a single disorder. All keratin isoforms share a common structure consisting of a central α-helical core flanked by two nonhelical domains of variable sequence, termed the E1/V1 (head) and the V2/E2 (tail) domains.25Omary MB Coulombe PA McLean WH Intermediate filament proteins and their associated diseases.N Engl J Med. 2004; 351: 2087-2100Crossref PubMed Scopus (371) Google Scholar Keratin intermediate filament assembly starts with the formation of keratin heterodimers always involving two designated partners, an acidic (type I) and a basic (type II) keratin molecule. In epidermal basal cells, KRT14 pairs with KRT5 to form the keratin cytoskeleton, which not only provides these cells with the ability to resist mechanical stress but also confers to them protection against proapoptotic signals.27Coulombe PA Omary MB 'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments.Curr Opin Cell Biol. 2002; 14: 110-122Crossref PubMed Scopus (518) Google Scholar The initial and terminal sequences of the central rod segment are extremely well conserved over evolution and play an important role during keratin intermediate filament assembly.25Omary MB Coulombe PA McLean WH Intermediate filament proteins and their associated diseases.N Engl J Med. 2004; 351: 2087-2100Crossref PubMed Scopus (371) Google Scholar In contrast, the variable V2 domain seems to be required for proper keratin filament supramolecular organization,23Sprecher E Ishida-Yamamoto A Becker OM Marekov L Miller CJ Steinert PM Neldner K Richard G Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 1164: 511-519Crossref Scopus (95) Google Scholar whereas the V1 domain is most probably involved in interactions between intermediate filaments and desmosomal proteins.28Candi E Tarcsa E Digiovanna JJ Compton JG Elias PM Marekov LN Steinert PM A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.Proc Natl Acad Sci USA. 1998; 95: 2067-2072Crossref PubMed Scopus (98) Google Scholar Missense mutations affecting the helix initiation and termination motifs of KRT5 or KRT14 cause EBS, which is characterized by the occurrence of intraepidermal blistering triggered by exposure of the skin to friction or trauma.17Rugg EL Leigh IM The keratins and their disorders.Am J Med Genet C Semin Med Genet. 2004; 131C: 4-11Crossref PubMed Scopus (41) Google Scholar, 25Omary MB Coulombe PA McLean WH Intermediate filament proteins and their associated diseases.N Engl J Med. 2004; 351: 2087-2100Crossref PubMed Scopus (371) Google Scholar Missense mutations within these conserved sites exert a dominant negative effect, leading to keratin clumping in basal cells, vacuolar degeneration, and cytoskeleton collapse on exposure to mechanical stress, which in turn causes cell cytolysis and intraepidermal blister formation. In contrast, mutations affecting the V1 and V2 domain of keratins 1 and 5 have been shown to result in unusual skin scaling/hyperkeratosis phenotypes and thus reveal distinct roles for these particular keratin subdomains.23Sprecher E Ishida-Yamamoto A Becker OM Marekov L Miller CJ Steinert PM Neldner K Richard G Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 1164: 511-519Crossref Scopus (95) Google Scholar, 24Betz RC Planko L Eigelshoven S Hanneken S Pasternack SM Bussow H Bogaert KV Wenzel J Braun-Falco M Rutten A Rogers MA Ruzicka T Nothen MM Magin TM Kruse R Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease.Am J Hum Genet. 2006; 78: 510-519Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 29Kimonis V DiGiovanna JJ Yang JM Doyle SZ Bale SJ Compton JG A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma.J Invest Dermatol. 1994; 103: 764-769Crossref PubMed Scopus (130) Google Scholar, 30Richardson ES Lee JB Hyde PH Richard G A novel mutation and large size polymorphism affecting the V2 domain of keratin 1 in an African-American family with severe, diffuse palmoplantar keratoderma of the ichthyosis hystrix Curth-Macklin type.J Invest Dermatol. 2006; 126: 79-84Crossref PubMed Scopus (32) Google Scholar In the present study, pathogenic mutations, uniquely located within the KRT14 E1/V1-encoding region, were identified in five families affected with NFJS/DPR. All mutations are predicted to generate premature termination codons (PTC) in the immediate vicinity of the KRT14 translation initiation site. Similarly, heterozygous nonsense mutations located in a corresponding region of KRT5 were recently found in the autosomal dominant skin disorder Dowling-Degos disease (MIM 179850), which is characterized by reticulate hyperpigmentation and small, hyperkeratotic, dark brown papules, involving flexural skin.24Betz RC Planko L Eigelshoven S Hanneken S Pasternack SM Bussow H Bogaert KV Wenzel J Braun-Falco M Rutten A Rogers MA Ruzicka T Nothen MM Magin TM Kruse R Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease.Am J Hum Genet. 2006; 78: 510-519Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar In addition, a recurrent missense mutation, P25L, affecting the V1 domain of KRT5 has been identified in many unrelated patients with a rare EB subtype, epidermolysis bullosa simplex with mottled pigmentation (MIM 131960)31Shurman D Losi-Sasaki J Grimwood R Kivirikko S Tichy E Uitto J Richard G Epidermolysis bullosa simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date.Eur J Dermatol. 2006; 16: 132-135PubMed Google Scholar; recently, a heterozygous missense mutation in KRT14 was described in a young patient with the same disease.32Harel A Bergman R Indelman M Sprecher E Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14.J Invest Dermatol. 2006; 126: 1654-1657Crossref PubMed Scopus (35) Google Scholar Combined with our current data, these observations provide convincing evidence that mutations in basal keratin genes can cause both blistering and pigmentary disorders of the skin. Intriguingly, biallelic nonsense mutations in KRT14 have been shown, in rare cases, to underlie autosomal recessive epidermolysis bullosa simplex (MIM 601001),33Has C Chang YR Volz A Hoeping D Kohlhase J Bruckner-Tuderman L Novel keratin 14 mutations in patients with severe recessive epidermolysis bullosa simplex.J Invest Dermatol. 2006; 126: 1912-1914Crossref PubMed Scopus (15) Google Scholar although no clinical abnormalities have been reported in the heterozygous carriers of these mutations. We therefore reexamined six heterozygous carriers of previously published recessive nonsense mutations in KRT14 (Q396X and W305X) and found that none displayed either abnormal pigmentation or any other skin abnormalities (unpublished data). The strikingly different phenotypic manifestations of recessive (EBS-causing) versus dominant (NFJS/DPR-causing) premature truncation mutations in KRT14 is puzzling and remains to be investigated. A possible explanation for these apparently discordant data could be provided by the different positions of the two types of mutations along the keratin molecule in NFJS/DPR versus EBS. Indeed, the dominant mutations identified in the subjects in this study with NFJS/DPR are confined to the initial 18 aa of the KRT14 molecule, whereas recessive EBS-causing mutations affect more-central or -distal regions of the protein (fig. 2c). NFJS-associated mutant KRT14 mRNA, in contrast with recessive EBS-associated transcripts, may be protected from nonsense-mediated degradation because of reinitiation of protein translation at a downstream alternative ATG, resulting in an N-terminally truncated protein, which in turn may possibly exert a dominant negative effect. Such a mechanism has been demonstrated in a number of recessive disorders.34McLean WH Irvine AD Hamill KJ Whittock NV Coleman-Campbell CM Mellerio JE Ashton GS Dopping-Hepenstal PJ Eady RA Jamil T Phillips RJ Shabbir SG Haroon TS Khurshid K Moore JE Page B Darling J Atherton DJ Van Steensel MA Munro CS Smith FJ McGrath JA An unusual N-terminal deletion of the laminin α3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome.Hum Mol Genet. 2003; 12: 2395-2409Crossref PubMed Scopus (105) Google Scholar, 35Paulsen M Lund C Akram Z Winther JR Horn N Møller LB Evidence that translation reinitiation leads to a partially functional Menkes protein containing two copper-binding sites.Am J Hum Genet. 2006; 79: 214-229Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar It is of note that Q7X could be identified by direct sequencing of RT-PCR products in cDNA extracted from a skin biopsy specimen that had been obtained from a patient of family 3 (not shown); thus, Q7X does not induce complete nonsense-mediated mRNA decay. Alternatively, the dominant premature truncation mutations in KRT14 reported in the present study could result in significantly shorter peptides than do recessive KRT14 mutations causing EBS. A steadily growing body of evidence indicates that acidic type I keratins (but not type II keratins or other intermediate filament proteins) may play an antiapoptotic role in keratinocytes through their interaction with TNF receptor type 1 (TNFR1)–associated death domain protein (TRADD).36Inada H Izawa I Nishizawa M Fujita E Kiyono T Takahashi T Momoi T Inagaki M Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD.J Cell Biol. 2001; 155: 415-426Crossref PubMed Scopus (129) Google Scholar, 37Yoneda K Furukawa T Zheng YJ Momoi T Izawa I Inagaki M Manabe M Inagaki N An autocrine/paracrine loop linking keratin 14 aggregates to tumor necrosis factor α-mediated cytotoxicity in a keratinocyte model of epidermolysis bullosa simplex.J Biol Chem. 2004; 279: 7296-7303Crossref PubMed Scopus (66) Google Scholar Experiments performed using truncated keratin molecules have shown that KRT18 is able to bind TRADD through the A1 coiled domain but not through the proximal E1/V1 domain.36Inada H Izawa I Nishizawa M Fujita E Kiyono T Takahashi T Momoi T Inagaki M Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD.J Cell Biol. 2001; 155: 415-426Crossref PubMed Scopus (129) Google Scholar It is conceivable that differences in the degree of keratin molecule truncation may affect the ability of the mutant protein to engage TRADD, which in turn may lead to an increase in apoptotic activity. The formation of apoptotic bodies and the presence of pigment incontinence in NFJS/DPR, as shown in figure 3c, supports this hypothesis. Moreover, apoptosis has also been observed in NFJS near sweat glands,15Frenk E Mevorah B Hohl D The Nageli-Franceschetti-Jadassohn syndrome: a hereditary ectodermal defect leading to colloid-amyloid formation in the dermis.Dermatology. 1993; 187: 169-173Crossref PubMed Scopus (9) Google Scholar which express KRT14 both in glandular tissues and in myoepithelial cells.38Langbein L Rogers MA Praetzel S Cribier B Peltre B Gassler N Schweizer J Characterization of a novel human type II epithelial keratin K1b, specifically expressed in eccrine sweat glands.J Invest Dermatol. 2005; 125: 428-444Crossref PubMed Scopus (61) Google Scholar Although in vitro experiments performed using a keratinocyte cell line have suggested that common KRT14 mutations may cause apoptosis,37Yoneda K Furukawa T Zheng YJ Momoi T Izawa I Inagaki M Manabe M Inagaki N An autocrine/paracrine loop linking keratin 14 aggregates to tumor necrosis factor α-mediated cytotoxicity in a keratinocyte model of epidermolysis bullosa simplex.J Biol Chem. 2004; 279: 7296-7303Crossref PubMed Scopus (66) Google Scholar we have been unable to find ultrastructural evidence for this phenomenon in 18 EBS cases, including 5 REBS cases, suggesting that increased apoptosis may be more specifically associated with NFJS. Therefore, two of the major features of NFJS/DPR, hypohidrosis and abnormal epithelial differentiation, could be explained by the marked abnormalities in keratin filament function and structure. The reason for the absence of dermatoglyphics in NFJS/DPR is another puzzle that remains to be solved. Dermatoglyphics develop during the first trimester of gestation as a consequence of proliferation of KRT14-expressing basal cells into the dermis.39Babler WJ Embryologic development of epidermal ridges and their configurations birth defects.Birth Defects Orig Artic Ser. 1991; 27: 95-112PubMed Google Scholar A number of rare monogenic disorders feature adermatoglyphia, such as dyskeratosis congenita (MIM 127550), Kabuki syndrome (MIM 147920), and Basan syndrome (MIM 129200). In addition, several cases of inherited isolated absence of dermatoglyphics have been reported,40Baird III, HW Kindred showing congenital absence of the dermal ridges (fingerprints) and associated anomalies.J Pediat. 1964; 64: 621-631Abstract Full Text PDF PubMed Scopus (17) Google Scholar, 41Dodinval P A propos de la dysplasie des crêtes épidermiques.Humangenetik. 1972; 15: 20-24PubMed Google Scholar for which KRT14 represents now a plausible candidate gene. In summary, we have identified dominant PTC mutations in the E1/V1-encoding region of KRT14 in five families with NFJS and DPR. These findings demonstrate that NFJS and DPR are allelic diseases, expand the spectrum of known keratin disorders, and suggest for the first time a role for KRT14 during the ontogenesis of sweat glands and dermatoglyphics. We are grateful to the family members for their enthusiastic, continuous, and generous participation in our study. We thank Vered Friedman and John Compton for support in nucleic acid analysis, Martin Hergersberg for his help with DNA extraction, and Alex Murray for her assistance with sample collection. This study was supported in part by grants provided by the Ruth and Allen Ziegler Fund for Pediatric Research (E.S.); by the Deutsche Forschungsgemeinschaft (H.C.H. and E.S.); and by the Bureau for Economic Growth, Agriculture, and Trade, Office of Economic Growth and Agricultural Development, U.S. Agency for International Development, under the terms of award TA-MOU-01-M21-023 (E.S., R.B., J.U., G.R.). Research was further funded in part by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS) grants AR38923 and K08-AR02141 (G.R. and J.U.) and by an FP6 grant from the European Union (Geneskin) (J.M.G.).
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