A Mutation in Human Keratin K6b Produces a Phenocopy of the K17 Disorder Pachyonychia Congenita Type 2

Smith, Frances J.D.; Jonkman, Marcel F.; Goor, H. van; Coleman, C. M.; Covello, S. P.; Uitto, Jouni; McLean, W.H. Irwin

doi:10.1093/hmg/7.7.1143

Cited by 156 publications

(128 citation statements)

References 19 publications

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“…6 The other cytokeratins of the CL are keratin pairs, K6a/ K16 and K6b/K17. 7 These keratin pairs are also expressed in the outer root sheath and, therefore, mutations in these keratins should result in disorders other than loose anagen.…”

Section: For Editorial Comment See Page 521mentioning

confidence: 99%

Is the Loose Anagen Hair Syndrome a Keratin Disorder?

Chapalain

Winter²,

Langbein³

et al. 2002

Arch Dermatol

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Section: For Editorial Comment See Page 521mentioning

confidence: 99%

Is the Loose Anagen Hair Syndrome a Keratin Disorder?

Chapalain

Winter²,

Langbein³

et al. 2002

Arch Dermatol

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“…This disease is an autosomal dominant ectodermal dysplasia caused by mutations in keratins K6, K16, and K17, whose major hallmark is hypertrophic nail dystrophy (6). Two main types of this disorder have been characterized: type I or the Jadassohn-Lewandowsky form, in which pachyonychia occurs in conjunction with palmoplantar keratoses and oral leukokeratoses (6,23), and type II or the Jackson-Lawler form, characterized by hair abnormalities and neonatal teeth but no oral lesions (6,24). The phenotype reported here displays some characteristics coincident with type I (tongue and palate lesions) and others with type II (incisor anomalies).…”

Section: Generation Of Transgenic Mice Expressing Bk6␤hk10 -Tomentioning

confidence: 83%

Severe Abnormalities in the Oral Mucosa Induced by Suprabasal Expression of Epidermal Keratin K10 in Transgenic Mice

Santos

Bravo

López

et al. 2002

Journal of Biological Chemistry

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Previous studies have demonstrated that keratin K10 plays an important role in mediating cell signaling processes, since the ectopic expression of this keratin induces cell cycle arrest in proliferating cells in vitro and in vivo. However, apart from its well known function of providing epithelial cells with resilience to mechanical trauma, little is known about its possible roles in nondividing cells. To investigate what these might be, transgenic mice were generated in which the expression of K10 was driven by bovine K6␤ gene control elements (bK6␤hK10). The transgenic mice displayed severe abnormalities in the tongue and palate but not in other K6-expressing cells such as those of the esophagus, nails, and hair follicles. The lesions in the tongue and palate included the cytolysis of epithelial suprabasal cells associated with an acute inflammatory response and lymphocyte infiltration. The alterations in the oral mucosa caused the death of transgenic pups soon after birth, probably because suckling was impaired. These anomalies, together with others found in the teeth, are reminiscent of the lesions observed in some patients with pachyonychia congenita, an inherited epithelial fragility associated with mutations in keratins K6 and K16. Although no epithelial fragility was observed in the bK6␤hK10 oral epithelia of the experimental mice, necrotic processes were seen. Collectively, these data show that the carefully regulated tissue-and differentiation-specific patterns displayed by the keratin genes have dramatic consequences on the biological behavior of epithelial cells and that changes in the specific composition of the keratin intermediate filament cytoskeleton can affect their physiology, in particular those of the oral mucosa.Keratin intermediate filaments (KIFs) 1 are present in the cytoplasm of all epithelial cells as heteropolymers of type I and type II keratin polypeptides. Type I and type II keratin genes display highly regulated expression patterns in a pairwise and differentiation-specific fashion (1-3). The role of KIF in epithelial cells and tissues remained elusive until the discovery, through studies with transgenic mice and the finding of mutations affecting keratin proteins in dominantly inherited epithelial fragility syndromes (4 -8), that keratins impart mechanical resilience to cells. This appears to be a function shared by the majority of the keratin family. Therefore, the changes in keratin expression observed during differentiation (or in certain situations such as in tumor growth or wound healing involving stratified epithelia) probably indicate subtle, cell type-specific differences in function among these polypeptides. Further keratin-specific functions should not be discarded.Previous studies have demonstrated that K10 has specific functions. This keratin replaces K14 as skin keratinocytes enter the terminal differentiation program and become postmitotic (9). In addition, K10 expression is severely reduced under hyperproliferative situations, such as in wound healing and epiderma...

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“…3,10 Pachyonychia congenita type 1 was originally linked to mutations in the type II keratin gene KRT6A and its type I expression partner KRT16 and PC-2 with mutations in KRT6B and KRT17. 3,4,6,8,11 Pachyonychia congenita has been genotyped at no cost in individuals who enroll in an international registry, enabling comprehensive genotype-phenotype analysis. [12][13][14][15][16] Phenotypic overlap among PC genotypes has now made obsolete the designations of PC-1 and PC-2.…”

mentioning

confidence: 99%

Pachyonychia Congenita in Pediatric Patients

et al. 2014

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IMPORTANCE Nail dystrophy in early childhood often suggests a diagnosis of pachyonychia congenita (PC). No previous investigation has focused on the early signs of PC and the natural course of the disease. OBJECTIVES To determine the course of pediatric PC, correlate the disease course with the clinical appearance and specific gene mutations, and assess the effect of pediatric PC on quality of life. DESIGN, SETTING, AND PARTICIPANTS One hundred one patients or families with genetically confirmed PC from the International Pachyonychia Congenita Research Registry who completed a survey on the general clinical features of PC and an auxiliary questionnaire on the clinical presentation and quality-of-life issues related to pediatric PC. EXPOSURE Individuals with pachyonychia congenita. MAIN OUTCOMES AND MEASURES Completion of both surveys. RESULTS At birth, toenail changes were present in 47.5% of patients; fingernail changes in 40.6%; and plantar keratoderma in 6.9%. By 5 years of age, these 3 key manifestations were found in 81.2%, 74.2%, and 75.3%, respectively, of individuals with genotype-confirmed PC. The correct diagnosis was made during the first year of life in 26.7% of patients despite the presence of toenail dystrophy in more than 65.3%. Clinical differences that distinguished PC subtypes included (1) later onset and less frequent occurrence of nail dystrophy and keratoderma in PC-K6b, PC-K6c, and PC-K16; (2) concurrent fingernail and toenail thickening in PC-K6a and PC-K17; (3) more palmar keratoderma in PC-K16; (4) cysts primarily in PC-K17 and follicular hyperkeratoses primarily in PC-K6a; (5) hoarseness and/or oral leukokeratoses in the first year of life most often in PC-K6a; and (6) natal teeth exclusively in PC-K17. Among pediatric patients, PC affected the social interactions and function of adolescents most profoundly. CONCLUSIONS AND RELEVANCE Among patients with a detectable mutation, PC manifests with nail thickening and plantar keratoderma before school age in more than three-quarters of affected children, allowing early diagnosis. The highly visible nail changes and painful plantar thickening exert a psychosocial effect on most affected adolescents. Phenotype-genotype correlations in children with PC validate the new classification based on the affected gene.

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A Mutation in Human Keratin K6b Produces a Phenocopy of the K17 Disorder Pachyonychia Congenita Type 2

Cited by 156 publications

References 19 publications

Is the Loose Anagen Hair Syndrome a Keratin Disorder?

Is the Loose Anagen Hair Syndrome a Keratin Disorder?

Severe Abnormalities in the Oral Mucosa Induced by Suprabasal Expression of Epidermal Keratin K10 in Transgenic Mice

Pachyonychia Congenita in Pediatric Patients

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