RESUMO
Skin identity is controlled by intrinsic features of the epidermis and dermis and their interactions. Modifying skin identity has clinical potential, such as the conversion of residual limb and stump (nonvolar) skin of amputees to pressure-responsive palmoplantar (volar) skin to enhance prosthesis use and minimize skin breakdown. Greater keratin 9 (KRT9) expression, higher epidermal thickness, keratinocyte cytoplasmic size, collagen length, and elastin are markers of volar skin and likely contribute to volar skin resiliency. Given fibroblasts' capacity to modify keratinocyte differentiation, we hypothesized that volar fibroblasts influence these features. Bioprinted skin constructs confirmed the capacity of volar fibroblasts to induce volar keratinocyte features. A clinical trial of healthy volunteers demonstrated that injecting volar fibroblasts into nonvolar skin increased volar features that lasted up to 5 months, highlighting a potential cellular therapy.
Assuntos
Melhoramento Biomédico , Bioimpressão , Derme , Epiderme , Fibroblastos , Queratinócitos , Adulto , Feminino , Humanos , Masculino , Amputados , Diferenciação Celular , Colágeno/metabolismo , Derme/citologia , Derme/metabolismo , Elastina/metabolismo , Epiderme/metabolismo , Fibroblastos/citologia , Fibroblastos/transplante , Mãos , Queratina-9/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Melhoramento Biomédico/métodosRESUMO
BACKGROUND: Palmoplantar pustulosis (PPP) and pompholyx are chronic diseases characterized by pustules and vesicles on the palms and soles. These disorders often have similar clinicopathological features, which lead to diagnostic difficulties. We aimed to investigate the expression patterns of keratins and involucrin in PPP and pompholyx using immunohistochemical staining. METHODS: Skin biopsies from patients with PPP (n = 40) and pompholyx (n = 22) were immunohistochemically analyzed for Keratin 5, 9, 14, and involucrin expression. RESULTS: K5 expression was higher in PPP than in pompholyx, with diffusely positive expression in the basal, spinous, and granular layers. K14 expression did not differ between groups. K9 expression was observed near the pompholyx vesicle (P = 0.014) and stratum spinosum (P < 0.001) but was almost absent around PPP pustules. Involucrin expression was diffused around the PPP pustules and partially around the pompholyx vesicles, but without statistical significance (P = 0.123). Involucrin expression was elevated in the basal layer of the PPP compared with that in the pompholyx (P = 0.023). CONCLUSION: PPP and pompholyx exhibited distinctive differentiation in the expression of K5, K9, and involucrin.
Assuntos
Imuno-Histoquímica , Queratinas , Precursores de Proteínas , Psoríase , Humanos , Precursores de Proteínas/metabolismo , Precursores de Proteínas/análise , Psoríase/metabolismo , Psoríase/patologia , Psoríase/diagnóstico , Masculino , Feminino , Queratinas/metabolismo , Queratinas/análise , Pessoa de Meia-Idade , Adulto , Diagnóstico Diferencial , Idoso , Adulto Jovem , Eczema Disidrótico/diagnóstico , Eczema Disidrótico/metabolismo , Eczema Disidrótico/patologia , Biópsia , Adolescente , Pele/patologia , Pele/metabolismo , Queratina-9/metabolismo , Queratina-9/análise , Queratina-14/metabolismo , Queratina-14/análiseRESUMO
Epidermolytic palmoplantar keratoderma (EPPK), a highly penetrant autosomal dominant genodermatosis, is characterized by diffuse keratoses on palmplantar epidermis. The keratin 9 gene (KRT9) is responsible for EPPK. To date, phenotypic therapy is the primary treatment for EPPK. Because KRT9 pairs with a type II keratin-binding partner to function in epidermis, identifying the interaction partner is an essential first step in revealing EPPK pathogenesis and its fundamental treatment. In this study, we proved that keratin 6C (KRT6C) is a probable hereterodimer partner for KRT9. In silico model for KRT6C/KRT9 shows a typical coiled-coil structure in their 2B domains. Proteomics analysis shows that KRT6C/KRT9 pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating cytoskeleton organization and keratinization. This study shows that co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis provide a sensitive approach, which compensates for inevitable inadequacies of anti-keratin 6C antibody and helps discover the probable hereterodimer partner KRT6C for KRT9. The acknowledgement of KRT6C/KRT9 pairwise relationship may help re-classify EPPK and PC-K6c (a milder form of pachyonychia congenita, caused by KRT6C) as a group of hereditary defects at a molecular-based level, and lay foundation for deciphering the keratin network contributing to EPPK and PC-K6c. SIGNIFICANCE OF THE STUDY: What is already known about this topic? KRT9 and KRT6C are disease-causing factors for epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c), respectively. EPPK and PC-K6c have some symptom similarities. Keratins are the major structural proteins in epithelial cells. Each of the type I keratin is matched by a particular type II keratin to assemble a coiled-coil heterodimer. The hereterodimer partner for KRT9 is unknown. What does this study add? We discovered and proved that KRT6C is a probable hereterodimer partner for KRT9 in palmplantar epidermis in a native endogenous environment by using co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis, etc. The proteomics analysis shows that KRT6C/KRT9 keratin pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating intermediate filament-based cytoskeleton organization and keratinization processes. What are the implications of this work? The new understanding of probable KRT6C/KRT9 pairwise correlation may help re-classify the genetic cutaneous disorders EPPK and PC-K6c as a group of hereditary defects at a molecular-based level, and lay foundation for pathogenic mechanism research in EPPK and PC-K6c. The densely related network components derived from the proteomic data using Metascape in the study and pairwise regulation fashion of specific keratin pairs should attract more attention in the further explorations when investigators concern the physiological functions of keratins and the pathogenesis of related skin diseases.
Assuntos
Ceratodermia Palmar e Plantar Epidermolítica , Paquioníquia Congênita , Humanos , Ceratodermia Palmar e Plantar Epidermolítica/genética , Ceratodermia Palmar e Plantar Epidermolítica/patologia , Proteômica , Epiderme , Queratinas/genética , Queratinas Tipo II/genética , Mutação , Linhagem , Queratina-9/genéticaAssuntos
Ceratodermia Palmar e Plantar Epidermolítica , Ceratodermia Palmar e Plantar , Humanos , População do Leste Asiático , Queratina-9/genética , Queratinas , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar Epidermolítica/diagnóstico , Ceratodermia Palmar e Plantar Epidermolítica/genética , Mutação , Mutação de Sentido Incorreto , Linhagem , Deleção de SequênciaRESUMO
PURPOSE: The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. METHODS: This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. RESULTS: There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. CONCLUSION: The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Queratina-7/metabolismo , Queratina-9/metabolismo , Neoplasias Bucais , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Carcinoma de Células Escamosas/patologia , Humanos , Queratina-7/análise , Neoplasias Orofaríngeas/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Palmoplantar skin has several unique characteristics such as increased thickness, high resilience, hypopigmentation, and lack of hair follicles. The establishment of palmoplantar identity occurs through keratinocyteâfibroblast interactions, with keratin 9 expression and Wnt signaling playing key roles. Understanding how palmoplantar features develop may help efforts to reproduce them at both palmoplantar and nonpalmoplantar body sites.
Assuntos
Fibroblastos/metabolismo , Queratinócitos/metabolismo , Pele/crescimento & desenvolvimento , Animais , Pé , Mãos , Humanos , Queratina-9/metabolismo , Camundongos , Modelos Animais , Pele/citologia , Pele/metabolismo , Pigmentação da Pele , Via de Sinalização WntAssuntos
Ceratodermia Palmar e Plantar Epidermolítica/genética , Serpinas/genética , Adulto , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Queratina-9/genética , Ceratodermia Palmar e Plantar Epidermolítica/patologia , Masculino , Mutação , Linhagem , Pele/patologia , Adulto JovemRESUMO
FoxN1 gene belongs to the forkhead box gene family that comprises a diverse group of "winged helix" transcription factors that have been implicated in a variety of biochemical and cellular processes. In the brown planthopper (BPH), FoxN1 is highly expressed in the ovaries and newly laid eggs, where it acted as an indispensable gene through its molecular targets to regulate early embryonic development. Moreover, the results of the RNAi experiments indicated that Nilaparvata lugens FoxN1 (NlFoxN1) exhibited pleiotropism: they not only affected the embryogenesis, but also played an important role in molting. RNA-seq and RNAi were further used to reveal potential target genes of NlFoxN1 in different stages. In the eggs, ten downregulated genes were defined as potential target genes of NlFoxN1 because of the similar expression patterns and functions with NlFoxN1. Knockdown of NlFoxN1 or any of these genes prevented the development of the eggs, resulting in a zero hatchability. In the nymphs, NlFoxN1 regulated the expression of a keratin gene, type I cytoskeletal keratin 9 (NlKrt9), to participate in the formation of an intermediate filament framework. Depletion of NlFoxN1 or NlKrt9 in nymphs, BPHs failed to shed their old cuticle during nymph-to-nymph or nymph-to-adult molting and the mortality was almost 100%. Altogether, the pleiotropic roles of NlFoxN1 during embryogenesis and nymph molting were supported by the ability to coordinate the temporal and spatial gene expression of their target genes.
Assuntos
Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica/veterinária , Hemípteros/fisiologia , Queratina-9/genética , Animais , Desenvolvimento Embrionário , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Hemípteros/metabolismo , Muda , Ninfa/fisiologia , Ovário/metabolismo , Interferência de RNA , Análise de Sequência de RNA/veterináriaRESUMO
BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is characterized by hyperkeratotic lesions on palms and soles. The disorder is caused by mutations of keratin 9 (KRT9) or KRT1 gene. METHODS: Epidermolytic palmoplantar keratoderma was diagnosed by physical examination and histopathological analysis in a five-generation Chinese family. Mutation was screened by Sanger sequencing. The palmar expression of multiple cytokeratins were analyzed by tape-stripping and Real-time PCR. Literatures of EPPK with additional symptoms were reviewed. RESULTS: Affected family members showed diffuse palmoplantar keratosis, with knuckle pads, friction-related lesions and a novel additional symptom of palmar constriction. A heterozygous mutation of c.T491C (p.L164P) of KRT9 was found within the helix initiation motif. The hydrophobic effect was decreased and the initiation of coiled-coil conformation was delayed. The KRT16/KRT6 expression were significantly increased in the patients, especially on the right, indicating activation of stress-response and wound-healing cytokeratins. There were also increased KRT9/KRT2, unchanged KRT10/KRT1, and undetectable KRT14/KRT5 expression. The genetic and phenotypic heterogeneity of EPPK with additional symptoms were summarized by literature review. CONCLUSION: The p.L164P mutation of KRT9 caused EPPK with a novel symptom of palmar constriction. The expression of multiple cytokeratins was altered in EPPK patients.
Assuntos
Povo Asiático/genética , Queratina-9/genética , Ceratodermia Palmar e Plantar Epidermolítica/genética , Ceratodermia Palmar e Plantar Epidermolítica/patologia , Mutação , Estudos de Casos e Controles , Feminino , Seguimentos , Heterozigoto , Humanos , Lactente , Masculino , LinhagemRESUMO
The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.
Assuntos
Queratina-16/genética , Queratina-9/metabolismo , Queratinócitos/citologia , Ceratodermia Palmar e Plantar/genética , Animais , Diferenciação Celular , Derme/efeitos dos fármacos , Derme/fisiopatologia , Células HeLa , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Isotiocianatos/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Queratina-16/metabolismo , Queratina-9/genética , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinas/metabolismo , Ceratodermia Palmar e Plantar/tratamento farmacológico , Ceratodermia Palmar e Plantar/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Mutação de Sentido Incorreto , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Sulfóxidos , Análise Serial de TecidosRESUMO
BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is a rare skin disorder and its pathogenesis and inheritability are unknown. OBJECTIVE: To investigate the inheritance and pathogenesis of EPPK. METHODS: Two EPPK cases occurred in a three-generation Chinese family. Patient-parents trio EPPK was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: A heterozygous missense pathogenic variant, c.488G > A (p.Arg163Gln), in the keratin (KRT) 9 gene was detected in the proband and his son via targeted exome sequencing, and then validated by Sanger sequencing. This pathogenic variant cosegregated with the EPPK in extended family members, and was predicted to be pathogenic by SIFT, PolyPhen2, PROVEAN, and Mutation Taster. This heterozygous variation was not evident in 100 healthy controls. CONCLUSION: This report describes a KRT9 c.488G > A (p.Arg163Gln) variant causing a diffuse phenotype of Chinese EPPK. The current results broaden the spectrum of KRT9 pathogenic variants responsible for EPPK and have important implications for molecular diagnosis, treatment, and genetic counseling for this family.
Assuntos
Povo Asiático/genética , Queratina-9/genética , Ceratodermia Palmar e Plantar Epidermolítica/genética , Adulto , China , Análise Mutacional de DNA , Heterozigoto , Humanos , Ceratodermia Palmar e Plantar Epidermolítica/patologia , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Pele/patologiaRESUMO
How cell and tissue identity persist despite constant cell turnover is an important biologic question with cell therapy implications. Although many mechanisms exist, we investigated the controls for site-specific gene expression in skin, given its diverse structures and functions. For example, the transcriptome of in vivo palmoplantar (i.e., volar) epidermis is globally unique, including Keratin 9 (KRT9). Although volar fibroblasts have the capacity to induce KRT9 in nonvolar keratinocytes, we show here that volar keratinocytes continue to express KRT9 in in vitro solo cultures. Despite this, KRT9 expression is lost with volar keratinocyte passaging, despite stable hypomethylation of its promoter. Coincident with KRT9 loss is a gain of the primitive keratin 7 and a signature of dsRNA sensing, including the double-stranded RNA (dsRNA) receptor DExD/H-Box Helicase 58 (DDX58/RIG-I). Exogenous dsRNA inhibits KRT9 expression in early passage volar keratinocytes or in vivo footpads of wild-type mice. Loss of DDX58 in passaged volar keratinocytes rescues KRT9 and inhibits KRT7 expression. Additionally, DDX58-null mice are resistant to the ability of dsRNA to inhibit KRT9 expression. These results show that the sensing of dsRNA is critical for loss of cell-specific gene expression; our results have important implications for how dsRNA sensing is important outside of immune pathways.
Assuntos
Regulação da Expressão Gênica , Queratina-9/genética , Queratinócitos/metabolismo , RNA de Cadeia Dupla/genética , RNA/genética , Animais , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Queratina-9/biossíntese , Queratinócitos/citologia , Camundongos , RNA de Cadeia Dupla/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND/AIMS: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis. It is characterized by diffuse yellow keratoses on the palmoplantar epidermis, with an erythematous border. The keratin 9 gene (KRT9) and less frequently the keratin 1 gene (KRT1) are responsible for EPPK. This study aims to identify and analyse genetic defects responsible for EPPK in a Han Chinese pedigree. METHODS: A four-generation Han Chinese pedigree containing five individuals affected with EPPK was recruited. Exome sequencing, Sanger sequencing, and bioinformatics tools were conducted to identify the mutation in this pedigree. HaCaT cells were transfected with either wild-type or mutated KRT9. Confocal laser immunofluorescence assay, imaging processing, and statistical analysis were performed to evaluate wild-type and mutant KRT9 groups. RESULTS: A novel heterozygous c.1369C>T transition (p.Leu457Phe) in exon 6 of the KRT9 gene was identified in four patients. It co-segregated with the disorder in the family. Functional analysis showed that withdrawal of the filament network from the cell periphery and particle formation were present in about 10% of Leu457Phe-transfected HaCaT cells, while approximately 3% of cells transfected with wild-type KRT9 showed this phenotype. The particles in mutant group were larger than that in wild-type group (P-value < 0.05). CONCLUSION: The variant may be the disease-causing missense mutation and produce dominant negative effects by interrupting keratin network formation. This study indicates the pathogenic role of the KRT9 gene mutation in this pedigree with EPPK, and may be helpful in genetic counseling, prenatal diagnosis and gene-targeted therapies of EPPK.
Assuntos
Queratina-9/genética , Ceratodermia Palmar e Plantar Epidermolítica/genética , Mutação de Sentido Incorreto , Adulto , Idoso , Sequência de Aminoácidos , Animais , Povo Asiático/genética , Linhagem Celular , Feminino , Humanos , Queratina-9/química , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de SequênciaRESUMO
A pull-down experiment (co-immunoprecipitation) was performed on a T24 human bladder cancer cell lysate treated with the Hsp inhibitor VER155008 using an Hsp70 antibody attached to Dynabeads. Keratin 9, a cytoskeleton intermediate filament protein, was identified by LC MS/MS analysis. This novel finding was confirmed by Western blotting, RT-PCR, and immunocytochemistry. Other members of the keratin family of proteins have been shown to be involved in cancer progression, most recently identified to be associated with cell invasion and metastasis. The specific role of keratin 9 expression in these cells is yet to be determined.
Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Queratina-9/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida , Humanos , Imunoprecipitação , Queratina-9/genética , Nucleosídeos de Purina , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Mutations of keratin 9 (KRT9) gene is a hot research area of epidermolytic palmoplantar keratoderma (EPPK). AIMS: To identify the genes caused the EPPK of a Chinese family. PATIENTS/METHODS: Three cases of lesions were collected for pathological examination. Genomic DNA was extracted from peripheral blood samples of six patients and five healthy individuals and 100 unrelated individuals. Polymerase chain reaction (PCR) was used to amplify exons 1 of KRT9 gene. PCR products were sequenced to identify potential mutations. RESULTS: The lesion pathology of the proband and two ill relatives diagnosed EPPK. A new heterozygous missense mutation (488G>T) was identified in the 488 site of exon 1 of KRT9 gene in all six patients, which resulted in substitution of thymine for guanine, and substitution of leucine acid for arginine acid at position 163 of the KRT9 protein. The same mutation was not found in the five healthy individuals of the family and 100 unrelated individuals. CONCLUSIONS: The new heterozygous missense mutation (488G>T) of KRT9 gene is probably the cause of EPPK in this Chinese family.
Assuntos
Povo Asiático/genética , Queratina-9/genética , Ceratodermia Palmar e Plantar Epidermolítica/genética , Mutação de Sentido Incorreto , Adulto , Feminino , Humanos , Ceratodermia Palmar e Plantar Epidermolítica/patologia , Masculino , LinhagemRESUMO
Epidermolytic palmoplantar keratoderma (EPPK) is a rare autosomal dominant skin disorder characterized by diffuse hyperkeratosis on the palms and soles. Whole-exome sequencing (WES) has become a powerful tool for the detection of rare causal variants of Mendelian disorders. However, no causal gene for EPPK in the Uygur population has been identified until now, and no treatment exists than can address the underlying pathology.WES analysis was undertaken on two individuals from a large Uygur EPPK pedigree whose disease locus mapped to 17q21.2 (chr:38994621-39893408) following previous linkage analysis. KRT9 (NM_000226.3:c.487C>T, p.Arg163Trp), and KRT15 (XM_005257346.1:c.212G>T, XP_005257403.1:p.Gly71Val) located in this region, have been identified as two candidate causative genes for EPPK in the Uygur family. Sanger sequencing was conducted on this region in other affected individuals (n = 38) from this family, non-affected individuals (n = 56) from this family and 100 unrelated controls. The missense mutation KRT9 c.487C>T, identified in this large Uygur population, is a potential causative mutation. To date, EPPK has no effective therapy, and siRNA is a potential avenue for EPPK therapy. To investigate this, full-length wild-type Keratin9 (KRT9; pKRT9-WT) and p.Arg163Trp (pKRT9-R163W) were then transfected into HaCaT cells. The small interfering RNAs targeting the KRT9 R163W mutant and wildtype KRT9 were transfected into HaCaT cells, and total RNA isolated at 72 h post-transfection. Quantitative polymerase chain reaction and western blotting were used to analyse the effects of knock-down on KRT9 mRNA and protein levels, respectively. siRNA was shown to specifically inhibit mutant KRT9 mRNA and protein expression (p < 0.01, with 95% confidence limits). Our study suggests that KRT9 is a causal gene for EPPK. This information is helpful for understanding the pathogenesis of EPPK in the Uygur population and raises the possibility of designing a novel siRNA treatment strategy for this population of EPPK patients.