A novel frameshift truncation mutation in the V2 tail domain of KRT1 causes mild ichthyosis hystrix of Curth–Macklin

Ichthyosis hystrix, Curth–Macklin type (IHCM) is an extremely rare autosomal dominant dermatosis caused by mutations in the keratin genes, KRT1 or KRT10, which often manifests as extensive, dark, spiky or verrucous plaques and severe palmoplantar keratoderma. We report a novel frameshift truncation mutation, c.1596_1597insAT (p.Gly533Metfs*82) in exon 7 (V2 tail domain) of KRT1, which, by replacing the glycine–serine-rich tail of KRT1 with a series of 75 alanine-rich amino acids, produces a mild IHCM phenotype. The patient with the mutation presented with localized ichthyosis and progressive hyperkeratosis of the palms and soles with no history of blistering.     

Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice‐site mutation in KRT10

Epidermolytic ichthyosis (EI; MIM 113800), previously named bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases. 1 EI is caused by dominant mutations in either KRT1 or KRT10, encoding keratin 1 (K1) and keratin 10 (K10), respectively. 1 Usually, mutations are missense substitutions into the highly conserved α‐helical rod domains of the proteins. 2 , 3 However, three inbred pedigrees in which EI is transmitted as a recessive trait due to KRT10 null mutations have been described. 4 - 6     

KRT9基因突变所致表皮松解性掌跖角化病1例

报告KRT9基因突变所致表皮松解性掌跖角化病1例.患者男,中国籍,32岁,手足角化性斑块30余年.皮肤科检查:双侧掌跖面可见对称性弥漫性角化斑块,皮肤粗糙增厚,呈灰黄色.皮损组织病理:表皮明显角化过度,颗粒层棘层增厚,皮突延长,颗粒细胞变性,考虑掌跖角化病.基因全外显子组测序结果:KRT9基因外显子检测出c.487C＞...     

Analysis of the KRT9 Gene in a Mexican Family with Epidermolytic Palmoplantar Keratoderma

Epidermolytic palmoplantar keratoderma (EPPK), an autosomal‐dominant genodermatosis, is the most frequently occurring hereditary palmoplantar keratoderma. EPPK is characterized by hyperkeratosis of the palms and soles. Approximately 90% of patients present with mutations in the KRT9 gene, which encodes for keratin 9. Many of these mutations are located within the highly conserved coil 1A region of the alpha‐helical rod domain of keratin 9, an important domain for keratin heterodimerization. The objective was to assess the clinical and molecular characteristics of a Mexican family with EPPK. The clinical characteristics of members of this family were analyzed. The KRT9 gene of affected members was polymerase chain reaction amplified from genomic DNA and sequenced. All affected members of the family had hyperkeratosis of the palms and soles with knuckle pads. The R163W mutation in the KRT9 gene was present in all affected individuals who were tested. Although R163W is the most frequent KRT9 mutation in patients with EPPK, only two families have been reported with knuckle pads associated with this mutation. Our findings indicate that knuckle pads can be associated with EPPK and the R163W mutation in a family with a genetic background different from that described here.     

Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis

Since 1994, four cases of epidermal nevus with epidermolytic hyperkeratosis (EH) caused by keratin 10 gene mutations have been reported, although no keratin 1 (K1) gene mutation has yet been reported. We detected a K1 gene (KRT1) mutation in epidermal nevus with EH in a 10-year-old Japanese male. The patient showed well-demarcated verrucous, hyperkeratotic plaques mainly on the trunk, covering 15% of the entire body surface. No hyperkeratosis was seen on the palms or soles. He had no family history of skin disorders. His lesional skin showed typical granular degeneration and, ultrastructurally, clumped keratin filaments were observed in the upper epidermis. Direct sequence analysis of genomic DNA extracted from lesional skin revealed a heterozygous 5' donor splice site mutation c.591+2T>A in KRT1. This mutation was not detected in genomic DNA samples from the patient's peripheral blood leukocytes or those of other family members. The identical splice mutation was previously reported in a family with palmoplantar keratoderma and mild ichthyosis, and was demonstrated to result in a 22 amino-acid deletion p.Val175_Lys196del in the H1 and 1A domains of K1. To our knowledge, the present patient is the first reported case of epidermal nevus associated with EH caused by a K1 gene mutation in a mosaic pattern.     

A novel mutation of keratin 9 gene (R162P) in a Japanese family with epidermolytic palmoplantar keratoderma

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant inherited skin disorder characterized by hyperkeratosis of the skin over the palms and soles. Mutations in keratin 9 gene (KRT9) have been demonstrated in EPPK. In this study, we screened a Japanese family with EPPK for KRT9 mutation by polymerase chain reaction amplification of genomic sequences, followed by heteroduplex analysis and direct nucleotide sequencing. The mutation consisted of a G-to-C transversion at codon 162 in exon 1, which was located in the hot spot of the mutations that have been reported previously (R162Q and R162W). However, the amino acid substitution was proline for arginine (R162P) in the 1A rod domain, the highly conserved helix initiation motif of keratin 9. Our result illustrates the repertoire of KRT9 mutation underlying the occurrence of EPPK in a Japanese family and is an important contribution to the investigation of the genotype/phenotype correlation.     

A keratin 9 Gene mutation (Asn160Ser) in a Japanese patient with epidermolytic palmoplantar keratoderma

We described a 5-year-old Japanese girl with epidermolytic palmoplantar keratoderma and examined her for a keratin 9 gene mutation. Physical examination disclosed diffuse yellowish hyperkeratosis with an erythematous border limited strictly to the palms and soles. Histological examination revealed hyperkeratosis with vacuolar degeneration in the spinous and granular layers of the epidermis. Sequence analysis demonstrated an A to G transition at the middle position of codon 160 in the 1A domain of the keratin 9 gene. The amino acid at codon 160 was deduced to have changed from asparagine (Asn) to serine (Ser). This is the first case with an Asn160Ser mutation in a Japanese. The substitution of Ser for Asn at codon 160 of the keratin 9 gene is assumed to be fatal for keratin filament assembly regardless of race or ethnicity.     

A novel mutation in the L12 domain of keratin 1 is associated with mild epidermolytic ichthyosis

Summary Background Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families. Objectives To investigate the effects of the novel KRT1:p.Asp340Gly and the one other previously reported KRT1:p.Asp340Val mutations on keratinocyte cytoskeleton formation and stress resistance. Methods Wild‐type and mutant pEGFP‐KRT1 fusion constructs were transfected into HaCaT cells and exposed to hypo‐osmotic shock. Haplotyping and genealogical studies were performed to investigate the possibility of a common founder for p.Asp340Gly. Results Cells transfected with either one of the keratin 1 L12 domain mutations showed significantly increased tonofilament aggregation. The haplotype around the KRT1 gene was shared in all affected family members of two families and a common founder was traced. Conclusions Our study supports the pathogenicity of the keratin 1 L12 domain mutations in vitro. These mutations are associated with a milder EI phenotype with pronounced palmoplantar keratoderma, and without neonatal erythroderma and scaling. The KRT1:p.Asp340Gly mutation in the Dutch families is likely to have arisen from a common founder.     

Generalized erythrosquamous dermatosis

A 21-year-old man presented with generalized erythema, erosions and hyperkeratoses since birth. Histology revealed epidermolytic hyperkeratosis with degeneration of the upper epidermis and perinuclear deposits of abnormal keratin aggregations. Epidermolytic ichthyosis was diagnosed. This congenital Ichthyosis occurs due to mutations of keratin 1 or 10 genes that leads to defects of intra- and intercellular structural integrity in the spinous and granular layers with compensatory hyperkeratosis. After childhood, life expectancy is normal but lifelong therapeutic and skin care measures are required.     

Identification of the keratin K9 R162W mutation in patients of Italian origin with epidermolytic palmoplantar keratoderma

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant skin disorder characterized by hyperkeratosis of the palms and soles associated with histologic findings of hyperkeratosis and epidermolysis. Ultrastructurally, there is vacuolization of the cytoplasm and abnormal keratin filament network with tonofilament clumping. EPPK is caused by mutations in the keratin 9 gene (KRT9), which is expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis. The mutation R162W is the most frequent keratin 9 alteration reported in patients from different geographical areas. We present three unrelated Italian families affected by EPPK in which we confirmed the presence of the R162W mutation, by RT-PCR analysis followed by sequencing of the KRT9 gene, in all affected members. The finding of the same mutation in all patients, together with the previous reports of the disease, strongly suggest that position 162 of the KRT9 gene represents a mutation "hot-spot", probably due to the peculiarity of the sequence.     

How do keratinizing disorders and blistering disorders overlap?

Inherited keratinizing disorders are caused by mutations in the genes encoding cornified cell envelope proteins, enzymes and their inhibitors, adhesion molecules, cytoskeletal proteins and others in the epidermis. These molecules are known to regulate differentiation, proliferation and cell adhesions. Intriguingly, some keratinizing disorders show blistering skin lesions, while some inherited blistering disorders show abnormal keratinization. Therefore, hereditary keratinizing and blistering diseases are closely related and show overlapping genetic backgrounds. In this review, we overviewed keratinizing and blistering disorders in terms of overlapping of the two disease groups. Gene mutations in desmosomal components cause striate keratoderma, Naxos disease, epidermolytic palmoplantar keratoderma and plakophilin deficiency, which first show skin fragility and blisters and later hyperkeratosis. Gene mutations in hemidesmosomal components cause various forms of epidermolysis bullosa, some of which show hyperkeratosis on the nails, palms and soles, in addition to blister formation. Diseases with gene mutations in calcium pump proteins are Darier disease and Hailey–Hailey disease, which show clinicopathological overlaps and develop both keratinizing and blistering skin lesions. Finally, gene mutations in epidermal keratins cause epidermolysis bullosa simplex, epidermolytic ichthyosis, superficial epidermolytic ichthyosis, epidermolytic palmoplantar keratoderma and pachyonychia congenita/focal palmoplantar keratoderma, which show thickening of the palms and soles with underlying blister formation. In general, responsible proteins for diseases developing both keratinizing and blistering conditions are adhesion molecules, calcium pump proteins and keratins, but not connexins, cornified cell envelop proteins, enzymes or inhibitors. It is still unknown how particular keratinizing diseases develop blisters and vice versa.     

Ichthyosis hystrix Curth–Macklin type in an African girl

Ichthyosis hystrix Curth–Macklin type is a rare autosomal dominant skin disorder characterized by extensive hyperkeratosis and palmo‐plantar keratoderma. It results from heterozygous frameshift mutation in keratin 1 gene (KRT1). Histological features, showing perinuclear vacuolization and binucleated cells, are similar to those of epidermolytic hyperkeratosis except for the absence of epidermolysis. The present report describes the condition in a 16‐year‐old African girl where available treatment was disappointing.     

Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene

BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis strictly confined to the palms and soles, and usually associated with mutations in the keratin K9 gene (KRT9). Mutations in the keratin K1 gene (KRT1) have been shown to underlie a variety of phenotypes typically involving generalized epidermolytic hyperkeratosis, but in some cases the phenotype can be more regionally restricted. OBJECTIVES: To identify the genetic defect in two unrelated families initially presenting with EPPK but where careful examination revealed hyperkeratosis extending on to the proximal wrist flexure. Methods Linkage analysis and DNA sequencing. RESULTS: We found that this phenotype is caused by a heterozygous missense mutation in the K1 gene, designated I479T. This mutation lies in the highly conserved helix termination motif of K1, previously shown to be important for keratin assembly and filament formation. In general, mutations in this region of keratins are associated with more severe disease phenotypes. However, K1 mutations in this region and the I479T mutation in particular have previously been associated with both severe and mild bullous congenital ichthyosiform erythroderma phenotypes. When further clinical enquiries were made, several affected individuals in the families studied here were found to have had transient flexural peeling and hyperkeratosis in the neonatal period. CONCLUSIONS: K1 mutations may underlie a phenotype closely resembling EPPK. A history of transient flexural peeling and hyperkeratosis in childhood and palmoplantar keratoderma which extends beyond the boundary of the palmoplantar margins may indicate a K1 mutation rather than a K9 defect. As K1 mutations are also associated with severe widespread phenotypes, with important implications for prognostic and genetic counselling, whole body examination is recommended for patients presenting with EPPK.     

Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation

The palmoplantar keratodermas (PPKs) are a large group of genodermatoses comprising nearly 60 genetically distinct diseases. They are characterized by hyperkeratosis on the palms and soles with or without extrapalmoplantar hyperkeratotic lesions. Focal PPK is one of the hallmarks of pachyonychia congenita, a rare autosomal dominant disorder resulting from mutations in the keratin genes KRT6A, KRT6B, KRT16 or KRT17. Recently, in-frame deletion mutations of KRT6C have been identified in three families with focal PPK with slight or no nail changes. We report here a novel KRT6C mutation identified in a Japanese family with PPK with phenotypic heterogeneity, presenting with not only focal but also diffuse hyperkeratosis. The proband had diffuse hyperkeratosis on the soles and small focal hyperkeratoses on the palms, while the two other affected individuals showed focal hyperkeratoses on the soles. All three patients were heterozygotes for c.1414G>A in KRT6C, predicted to result in p.Glu472Lys. These findings strongly suggest that screening of patients with nonepidermolytic diffuse PPK, in whom the pathogenic mutations are yet to be determined, might identify mutations in KRT6C.     

Mutations in the keratin 9 gene in Pakistani families with epidermolytic palmoplantar keratoderma

Background. Keratins are heteropolymeric proteins that form the intermediate filament cytoskeleton in epithelial cells. The common basic structure of all keratins is organized in a central α‐helical rod domain flanked by nonhelical, variable head and tail regions. Most mutations in keratins are found in the central α‐helical rod domain. Keratin 9 (K9) is expressed only in the suprabasal layers of palmoplantar epidermis. Mutations in the keratin 9 gene (KRT9) have been shown to cause epidermolytic palmoplantar keratoderma (EPPK; OMIM 144200), an autosomal dominant genodermatosis characterized clinically by diffuse hyperkeratosis limited to the palms and soles, and histologically by epidermolysis in suprabasal layers of the epidermis. Aim. To elucidate the genetic basis of EPPK in five Pakistani families. Methods. Using microsatellite markers localized to the areas around the type I keratin gene cluster on chromosome 17q21, genotyping of these families was performed, followed by sequencing of the KRT9 gene. Results. The analysis resulted in the identification of two novel (p.M157K and p.Y454H) and two recurrent (p.M157T and p.R163Q) mutations in the KRT9 of all five families. All mutations occurred within the highly conserved helix initiation or termination motif of K9. Conclusions. The affected members of all five families possess mutations in the KRT9 gene that severely affect heterodimer formation with the type II keratin partner. The results of our study further underscore the crucial role of K9 protein in the palmoplantar epidermis.     

Splice site and deletion mutations in keratin (KRT1 and KRT10) genes: unusual phenotypic alterations in Scandinavian patients with epidermolytic hyperkeratosis

Epidermolytic hyperkeratosis is a rare autosomal dominant inherited skin disorder caused by keratin 1 or keratin 10 mutations. Keratins are major structural proteins of the epidermis, and in keratinocytes committed to terminal differentiation the intermediate filaments are composed of keratin 1 and keratin 10 heterodimers. The majority of reported mutations (86.6%) are heterozygous single point mutations and most of these are located in the 1A and 2B regions of the highly conserved keratin alpha-helical rod domain. We have studied eight Scandinavian families with epidermolytic hyperkeratosis and identified three point mutations, two codon deletions, two splice site mutations, and a complex deletion/insertion. Two of the point mutations were in the KRT1 gene (F191C and K177N) and the other was in KRT10 (L453P). All three patients had associated palmoplantar keratoderma. The splice site mutations in KRT1 both caused a large deletion removing 22 codons (delta176-197) from the 1A helical domain. Codon deletions were found in KRT1 (delta170-173) and in KRT10 (delta161-162) in two patients with a severe phenotype. A final patient had a more complex mutation with a large deletion (442 bp) together with a large insertion (214 bp) of unknown origin that caused deletion of exon 6 in KRT1. In conclusion, we have found eight novel keratin mutations that cause epidermolytic hyperkeratosis with differing phenotypes. Even when a large part of keratin 1 (46 amino acids) is deleted, surprisingly mild phenotypes can result, suggesting that genotype-phenotype relationships in epidermolytic hyperkeratosis are complex and do not solely depend on the type of mutation but also depend on interactions between the behavior of the mutant protein and the cellular environment.     

Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis

Keratin intermediate filaments are expressed in specific type I/type II pairs in the stage of differentiation of keratinocytes. The mutations in the keratin genes expressed in the epidermis are etiologically responsible for several epidermal genetic skin diseases, such as epidermolysis bullosa simplex, epidermolytic hyperkeratosis (EHK), ichthyosis bullosa of Siemens, palmoplantar keratoderma, pachyonchia congenita and white sponge nevus. The mutations of keratins 1/10 which are expressed in spinous and granular layers are confirmed to cause EHK. There are several trials to correlate between the clinical phenotypes and sites of mutations of the keratin genes. One of these is that EHK is divided into two groups: the palms and soles involvement (PS) group and the non-palms and soles (NPS) group. So far the PS group had the mutations in the keratin 1 and the NPS group in keratin 10. Most of the mutations of the NPS group were reported in the beginning of the 1A rod domain and over 2/3 of the mutations in the 1A rod domain were the base pair substitution of arginine. Here we find two different mutations in two unrelated Korean kindreds classified as NPS group-R156C and R156H-in the 1A rod domain of keratin 10. Our results are compatible with the above classification and suggest that the arginine in the beginning of the 1A rod domain is the hot spot for the mutation of the keratin 10 gene.     

Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma

Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell‐fragility disorders, and are the genetic basis of many inherited palmoplantar keratodermas (PPKs). Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1. Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. We report four unrelated cases (one with sporadic EI and three with autosomal dominant PPK), due to two novel and two recurrent KRT1 mutations. Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern.     

Severe epidermolysis bullosa simplex phenotype caused by codominant mutations p.Ile377Thr in keratin 14 and p.Gly138Glu in keratin 5

Epidermolysis bullosa simplex (EBS) is a rare skin disease usually inherited in an autosomal dominant pattern. EBS is resulting from mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes encoding the keratins 5 and 14 proteins expressed in the keratinocytes of the basal layer of the epidermis. To date, seven pathogenic mutations have been reported to be responsible for EBS in the Canadian population from the province of Quebec: p.Pro25Leu, p.Leu150Pro, p.Met327Thr and p.Arg559X in KRT5; p.Arg125Ser, p.Ile377Thr and p.Ile412Phe in KRT14. Here, we present a novel French-Canadian patient diagnosed with EBS confined to the soles but presenting a severe complication form including blisters, hyperkeratosis, skin erosions and toenail abnormalities. Mutation screening was performed by direct sequencing of the entire coding regions of KRT5 and KRT14 genes and revealed the previously reported missense heterozygous mutation c. 1130T > C in KRT14 (p.Ile377Thr). Furthermore, this patient is carrying a second mutation in KRT5, c.413G > A (p.Gly138Glu), which has been linked to an increased risk of basal cell carcinoma in the literature. We suspect an impact of the p.Gly138Glu variant on the EBS phenotype severity of the studied patient. The pathogenicity and consequences of both genetic variations were simulated by in silico tools.