Alternative titles; symbols
HGNC Approved Gene Symbol: KRT5
SNOMEDCT: 254180002, 716700003;
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:52,514,575-52,520,394 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Dowling-Degos disease 1 | 179850 | Autosomal dominant | 3 |
| Epidermolysis bullosa simplex 2A, generalized severe | 619555 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 2B, generalized intermediate | 619588 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 2C, localized | 619594 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 2D, generalized, intermediate or severe, autosomal recessive | 619599 | Autosomal recessive | 3 | |
| Epidermolysis bullosa simplex 2E, with migratory circinate erythema | 609352 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 2F, with mottled pigmentation | 131960 | Autosomal dominant | 3 |
For background information on keratins, see KRT15 (148030).
The KRT5 gene encodes keratin-5, which together with keratin-14 (KRT14; 148066) form the intermediate filament (IF) cytoskeleton in basal keratinocytes of stratified epithelia. Keratin-5 belongs to the type II (basic) gene family of IF proteins; in epithelia, distinct pairs of type I (acidic) and type II proteins are expressed to form an IF cytoskeleton with unique mechanical properties (summary by Betz et al., 2006).
Lersch and Fuchs (1988) reported the cDNA and amino acid sequences of a human 58-kD type II keratin, K5, which is coexpressed with a 50-kD type I keratin, K14 (148040), in stratified squamous epithelia.
Eckert and Rorke (1988) cloned full-length KRT5 from a cultured keratinocyte cDNA library. The deduced 590-amino acid protein contains a central alpha-helical core region of about 310 amino acids with a 7-amino acid repeat found in coiled-coil structures. The N and C termini are serine-rich and contain gly-gly-gly-x motifs.
Mischke et al. (1990) showed that 2 electrophoretic variants for each of the human keratins K4 and K5 that are expressed in squamous nonkeratinizing epithelia lining the upper digestive tract could be distinguished by SDS-PAGE. K5 appears to have 2 codominant alleles, a and b. On the basis of a population sample, they concluded that the alleles are in Hardy-Weinberg equilibrium.
Trask et al. (1990) showed that normal mammary epithelial cells in culture produce keratins K5, K6 (see 148041), K7 (148059), K14, and K17 (148069), whereas tumor cells produced mainly keratins K8 (148060), K18 (148070), and K19 (148020).
Eckert and Rorke (1988) determined that the 5-prime region of the KRT5 gene contains a TATA box and a potential CAAT box. The 3-prime region contains a single polyadenylation signal.
Knox et al. (2010) hypothesized that parasympathetic innervation is required for epithelial progenitor cell function during organogenesis. Removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. Knox et al. (2010) demonstrated that acetylcholine signaling, via the muscarinic M1 receptor (118510) and epidermal growth factor receptor (131550), increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis.
In mice, Zuo et al. (2015) showed that preexisting, intrinsically committed distal airway stem cells expressing TRP63 (603273) and keratin-5, called DASC(p63/Krt5), undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. Zuo et al. (2015) also showed that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to prefibrotic lesions and deficient oxygen exchange. Finally, the authors demonstrated that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. Zuo et al. (2015) concluded that the ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.
Vaughan et al. (2015) independently defined the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells that are present within normal distal lung. The authors stated that quiescent LNEPs activate a delta-Np63 (a p63 splice variant) and cytokeratin-5 (Krt5) remodeling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signaling to activate the delta-Np63 and cytokeratin-5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signaling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signaling. Vaughan et al. (2015) concluded that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and that the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signaling.
Rosenberg et al. (1991) assigned the type II epidermal keratin gene KRT5 to chromosome 12 by use of Southern blot analysis of somatic cell hybrids. Bonifas et al. (1991) reported that a K5-specific human cosmid was localized to a position on chromosome 12 (12q11-q13) nearly indistinguishable from the location of D12S14 and D12S17 by 2-color fluorescence in situ hybridization. Inasmuch as epidermolysis bullosa simplex was found to be linked to D12S14 in 1 family, the very close localization of the KRT5 gene to D12S14 by multicolor fluorescence in situ hybridization supported KRT5 as a candidate gene (Bonifas et al., 1992).
Epidermolysis Bullosa Simplex
In affected members of a large family with epidermolysis bullosa simplex, severe type (EBS2A; 619555), formerly known as Dowling-Meara EBS, Lane et al. (1992) identified a heterozygous mutation in the KRT5 gene (E475G; 148040.0001).
In the large Finnish family with the generalized (Koebner) type of EBS (EBS2B; 619588), Dong et al. (1993) identified a heterozygous mutation in the KRT5 gene (L462P; 148040.0002).
In affected members of 2 unrelated families with localized epidermolysis bullosa simplex (EBS2C; 619594), Chan et al. (1993) identified a heterozygous mutation in the KRT5 gene (I161S; 148040.0003). Ehrlich et al. (1995) identified the I161S mutation in 6 of 13 cases of the localized type of EB simplex. The high frequency of this mutation suggested either a hotspot or founder effect.
Humphries et al. (1996) reported 2 large multigenerational Irish families (TCDN and TCDM) with the Weber-Cockayne form of EBS, both segregating heterozygous missense mutations in the KRT5 gene: M327T (148040.0004) in family TCDM, and N193K (148040.0007) in family TCDN. A missense mutation in the KRT14 gene (M272R; 148066.0007) had been identified previously in a 3-generation Irish family (TCDG) with the Koebner form of EBS (EBS1B; 131900) by Humphries et al. (1993). Noting that they knew of no other large families with EBS in the Irish population, Humphries et al. (1996) concluded that the M272R and N193K mutations in KRT5, together with the M272R variant in KRT14, likely accounted for most cases of dominant localized epidermolysis bullosa simplex in Ireland.
In a Japanese boy with generalized severe EBS, Nomura et al. (1996) identified heterozygosity for a de novo L174F substitution in the KRT5 gene (148040.0008).
In affected members of 2 unrelated families, one of whom was originally described by Fischer and Gedde-Dahl (1979), with epidermolysis bullosa simplex with mottled pigmentation (EBS2F; 131960), Uttam et al. (1996) identified a heterozygous mutation in the KRT5 gene (P24L; 148040.0009). Irvine et al. (1997) identified the P24L mutation in the sporadic case of a 6-year-old boy who showed acral blistering, mottled pigmentation of the limbs, and punctate hyperkeratoses primarily affecting the soles. The authors speculated that recurrence of this mutation may be related to the fact that it occurred in a CpG site. Although the mutation might explain the epidermolysis, the cause of the mottled pigmentation remained obscure.
In a Japanese girl with epidermolysis bullosa simplex with migratory circinate erythema (EBS2E; 609352) and affected members of an unrelated Korean family, Gu et al. (2003) identified heterozygosity for a 1-bp deletion (c.1649delG; 148040.0017) in the KRT5 gene. The patients had a phenotype that was less severe than that of EBS Dowling-Meara, with an unusual migratory circinate erythema and multiple vesicles on the erythematous area.
In 2 affected members of a Japanese family with epidermolysis bullosa simplex with mottled pigmentation (EBS2F), Horiguchi et al. (2005) detected heterozygosity for a 1-basepair deletion in exon 9 of the KRT5 gene (c.1649delG; 148040.0017) resulting in frameshift and extension of the protein. Horiguchi et al. (2005) noted that this mutation had previously been identified in patients with EBS with migratory circinate erythema (EBS2E; 609352) by Gu et al. (2003).
In a Mexican father, his 5 affected children, and a Finnish woman who all exhibited EBS with mottled pigmentation, Shurman et al. (2006) identified heterozygosity for the recurrent P25L mutation in the KRT5 gene. The authors noted that these were the first reported EBSMP patients of Hispanic or Finnish origin, and stated that this strongly refuted a founder effect in EBSMP.
In 2 Chinese sibs with EBS with mottled pigmentation and in their affected mother, Tang et al. (2009) detected heterozygosity for the c.1649delG mutation in KRT5.
In a 1-year-old girl who exhibited EBS with mottled pigmentation, Geller et al. (2013) identified heterozygosity for the c.1649delG mutation.
Yasukawa et al. (2002) reported an unusual Japanese family with EBS and 2 mutations in the KRT5 gene, resulting in phenotypic variability. The proband, who had generalized blistering and had been diagnosed with EBS Koebner type (see 619588), was compound heterozygous for E170K (148040.0020) and E418K (148040.0021) mutations in the KRT5 gene. Other family members who carried the E170K mutation in heterozygosity had localized blistering of the hands and feet and had been diagnosed with EBS Weber-Cockayne type (EBS2C; 619594). Two unaffected family members were heterozygous for the E418K substitution, implying that it is not pathogenic in isolation. Oldak et al. (2011), Gonzalez-Cantero et al. (2017), and Vahidnezhad et al. (2019) described families with similar transmission pattern of the E170K mutation; see 148040.0020.
In a 15-year review of all infants born with generalized severe EBS and notified to the National Health Service of the UK, Sathishkumar et al. (2016) identified 37 cases. Genetic analysis in 33 of those cases showed KRT5 mutations in 17 (see, e.g., 148040.0001 and 148040.0025), KRT14 mutations in 15, and mutations in both KRT5 and KRT14 in 1 patient. Patients with mutations in KRT5 included 2 with the E475G variant (148040.0001), and 7 with an E477K substitution (148040.0025). Of the 7 children with the E477K variant, 5 died in infancy. The authors suggested that the KRT5 E477K variant might predispose to a severe and potentially lethal form of severe generalized EBS.
Kumagai et al. (2017) reported affected individuals in 2 Japanese families who had EBS with migratory circinate erythema (EBS2E; 609352) and mutations in the KRT5 gene: in the first family, the proband, his father, and his paternal grandmother were heterozygous for a 4-bp deletion (148040.0026), and in the second family, a 3-year-old girl had a de novo occurrence of the recurrent c.1649delG mutation (148040.0017). All affected individuals displayed early-onset circinate erythema that spontaneously resolved, but then developed mottled pigmentation. The authors noted that both mutations resulted in deletion of C-terminal peptides of KRT5 in the V2 domain with the addition of frameshifted peptides with identical reading frames, and suggested that the shared frameshifted peptides contributed to the characteristic inflammatory phenotype by triggering immune reactions.
In a Korean boy with EBS who developed migratory circinate erythema at 9 years of age, Lee et al. (2018) identified heterozygosity for a de novo in-frame 12-bp deletion in the KRT5 gene (148040.0027). The mutation was not found in his unaffected parents or in public variant databases.
Lalor et al. (2019) ascertained 6 children from national or local epidermolysis bullosa databases, from the United States, Italy, Germany, Finland, and Chile, who were heterozygous for the E477K mutation in the KRT5 gene. All were severely affected and 1 infant died. In 5 patients, the mutation was demonstrated to have arisen de novo; genetic analysis had not yet been performed in the parents of the sixth patient.
Tryon et al. (2019) reported an infant with severe autosomal recessive generalized EBS (EBS2D; 619599) who was homozygous for a mutation in the KRT5 gene (148040.0022).
Vahidnezhad et al. (2019) reported 2 children with autosomal recessive generalized EBS (EBS2D; 619599) from consanguineous Syrian families who were homozygous for mutations in the KRT5 gene (148040.0023-148040.0024).
In a 2.5-year-old Turkish boy who had EBS with migratory circinate erythema (EBS2E; 609352), Yalici-Armagan et al. (2020) identified heterozygosity for a 1-bp deletion in the KRT5 gene (148040.0028), inherited from his affected mother. He was also heterozygous for a D197E substitution in KRT5, for which his unaffected father was homozygous; this variant was believed to be nonpathogenic.
Dowling-Degos Disease 1
Dowling-Degos disease-1 (DDD1; 179850) is an autosomal dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures. Betz et al. (2006) performed a genomewide linkage analysis of 2 German families and mapped DDD1 to chromosome 12q, with a total lod score of 4.42 (theta = 0.0) for marker D12S368. This region included the keratin gene cluster, which they screened for mutations. They identified loss-of-function mutations in the KRT5 gene (see, e.g., 148040.0018; 148040.0019) in all affected family members and in 6 unrelated patients with DDD1. This represented the first identified mutations that led to haploinsufficiency in a keratin gene. The identification of loss-of-function mutations, along with the results from additional functional studies, suggested a crucial role for keratin in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.
Susceptibility to Basal Cell Carcinoma
For discussion of a possible association between variation in the KRT5 gene and susceptibility to basal cell carcinoma, see BCC4 (613061).
Peters et al. (2001) found that Krt5-null mice died shortly after birth, lacked keratin filaments in the basal epidermis, and were more severely affected than Krt14 (148066)-null mice. In contrast to the Krt14-null mice, Krt5-null mice showed a strong induction of the wound-healing Krt6a (148041) in the suprabasal epidermis of cytolyzed areas. Krt5-null and Krt14-null mice also differed with respect to tongue lesions. In the absence of Krt5, residual Krt14 and Krt15 (148030) aggregated along hemidesmosomes, demonstrating that individual keratins without a partner can be stable in vivo. The data also indicated that Krt5 may be the natural partner of Krt15 and Krt17 (148069). The findings suggested that KRT5 null mutations may be lethal in human epidermolysis bullosa simplex patients.
Roth et al. (2009) found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19 (602227), and CCL20 (601960), all of which are regulated by NFKB (164011) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; 601045). Enhanced Langerhans cell recruitment within the epidermis was found in 5 human patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an first explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins.
In affected members of a large family with Dowling-Meara EBS (EBS2A; 619555), Lane et al. (1992) identified a heterozygous A-to-G transition in the KRT5 gene, resulting in a glu475-to-gly (E475G) substitution in a highly conserved position 3 residues before the end of the rod domain, in a sequence known as the helix termination peptide.
From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 2 patients who were heterozygous for the E475G mutation in the KRT14 gene.
In the large Finnish family with the generalized Koebner type of EBS (EBS2B; 619588) in which Ryynanen et al. (1991) found linkage to the type II keratin cluster on 12q, Dong et al. (1993) found a heterozygous mutation in KRT5. The disorder was associated with a T-to-C transition (CTG to CCG) within exon 7, resulting in substitution of leucine by proline at codon 462 (L462P). The substituted leucine is one that is invariant among 8 different human keratins in a highly conserved segment at the carboxy-terminal region of the keratin 5 polypeptide.
In affected members of 2 unrelated families with localized EBS (EBS2C; 619594), Chan et al. (1993) found a heterozygous T-to-G transversion in the second base position of codon 161 of 1 of the 2 K5 alleles, leading to a substitution of serine for isoleucine (I161S). Linkage analysis mapped the defect to 12q11-q13. Ehrlich et al. (1995) identified the same mutation in 6 of 13 cases of the Weber-Cockayne type of EB simplex. The high frequency of this mutation suggested either a hotspot or founder effect.
Pfendner et al. (2005) identified a heterozygous I161S mutation in a patient with blistering of the hands and feet. The patient's affected mother carried the same mutation.
In affected members in 3 generations of a family with localized EBS (EBS2C; 619594), Chan et al. (1994) identified a heterozygous met327-to-thr (M327T) mutation in KRT5. The mutation cosegregated with the disease, was located in the nonhelical linker segment L1-2, and perturbed the ability of keratin-5 to assemble with its partner into 10-nm filaments.
Humphries et al. (1996) identified a heterozygous M327T mutation in affected members of a large 6-generation Irish family (TCDM) with localized EBS.
Chan et al. (1994) found a heterozygous N329K mutation in the KRT5 gene as the cause of localized EBS (EBS2C; 619594) in a family with affected members in 2 generations. Like the M327T mutation (148040.0004), it was located in the nonhelical linker segment L1-2 of keratin 5 and perturbed the ability of keratin 5 to assemble with its partner into 10-nm filaments.
In a family with autosomal dominant generalized intermediate EBS (EBS2B; 619588), Stephens et al. (1995) demonstrated a mutation predicted to result in the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N). Unlike previous heterozygous mutations located within the initial segment of domain 1A of keratins, K173N heterozygosity did not result in severe disease or clumping of keratin filaments. One family member was homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. Despite a lack of normal keratin-5 molecules and an effective doubling of abnormal molecules available for heterodimerization with keratin-14 during formation of intermediate filaments (IFs), there were no significant differences from heterozygotes in either the clinical severity or the ultrastructural organization of the homozygous individual's keratin IF cytoskeleton. These data demonstrated that the K173N mutation behaves as a fully dominant allele. The findings indicated also that a limited number of abnormal keratin molecules are sufficient to impair cytoskeletal function and elicit epidermal fragility and blistering.
In affected members of a large 4-generation Irish family (TCDN) with localized EBS (EBS2C; 619594), Humphries et al. (1996) identified a heterozygous mutation in the KRT5 gene, resulting in an asn193-to-lys (N193K) substitution.
In a Japanese patient with epidermolysis bullosa simplex Dowling-Meara type (EBS2A; 619555), Nomura et al. (1996) identified a de novo heterozygous C-to-T transition in the KRT5 gene, resulting in a leu174-to-phe (L174F) substitution in the highly conserved 1A region within the helix initiation peptide. The mutation was not found in 40 healthy unrelated Japanese controls.
In 2 unrelated families with epidermolysis bullosa simplex with mottled pigmentation (EBS2F; 131960), one of which had been described originally by Fischer and Gedde-Dahl (1979), Uttam et al. (1996) found a heterozygous C-to-T transition at base position 71 of the KRT5 gene, causing a P24L substitution. The mutation occurred in the V1 domain of keratin 5; previous mutations of K5 or K14 (148066) reported in EBS had been located in the central helical rod domains, with a tendency to aggregate at the highly conserved helix boundary peptides or at the nonhelical L12 linker domain. Irvine et al. (1997) identified the same mutation in the sporadic case of a 6-year-old boy who showed acral blistering, mottled pigmentation of the limbs, and punctate hyperkeratoses primarily affecting the soles. The authors speculated that recurrence of this mutation may be related to the fact that it occurred in a CpG site. Although the mutation might explain the epidermolysis, the cause of the mottled pigmentation remained obscure.
Moog et al. (1999) noted that, at the time of their report, the P24L mutation of the KRT5 gene was the only mutation identified in patients with EBS-MP. Moog et al. (1999) described a sporadic patient and a family with an affected 6-year-old girl, her mother, and maternal aunt; all of them had the P24L mutation. The 6-year-old girl showed erythema with telangiectasia on the cheeks and above the upper lip at birth. From 6 months of age, blisters arose daily after minor trauma, predominantly on the distal extremities. The lesions healed without scarring. Over time, the tendency to blistering decreased considerably. However, her skin remained fragile on sites where adhesive tape was used. Hyperpigmented spots that were not preceded by blistering developed from infancy. The mother had mild blistering (always confined to the feet) and mottled pigmentation from infancy.
Irvine et al. (2001) reported the KRT5 pro25-to-leu mutation in 2 additional families, both originally described by Boss et al. (1981), increasing the total number of EBS-MP kindreds with this mutation to 7. This mutation was previously reported as PRO24LEU based on the numbering suggested by Lersch et al. (1989), which ignores the initial methionine. All other KRT5 mutations are numbered according to GenBank M21389, which includes methionine. Irvine et al. (2001) suggested that the P25L designation be used in future reports.
In a Mexican father, his 5 affected children, and a Finnish woman who all exhibited EBS with mottled pigmentation, Shurman et al. (2006) identified heterozygosity for the recurrent P25L mutation in the KRT5 gene. The authors noted that these were the first reported EBSMP patients of Hispanic or Finnish origin, and stated that this strongly refuted a founder effect for this mutation in EBSMP.
Glasz-Bona et al. (2010) identified a heterozygous P25L mutation in affected members of a 4-generation Hungarian pedigree with EBS-MP. There were 10 affected members, 5 of whom were deceased. All had localized blistering and skin fragility in childhood, followed by the development of brownish, lentigo-like mottled pigmentation and hypopigmentation on the trunk and/or extremities in adolescence and adulthood. Two patients also had nail dystrophy. In this family, the P25L mutation segregated with a gly138-to-glu (G138E) polymorphism.
In a family with the autosomal dominant generalized intermediate variant of epidermolysis bullosa simplex (EBS2B; 619588), Galligan et al. (1998) found a heterozygous T-to-C transition in codon 323 of KRT5 in affected individuals, resulting in a valine to alanine substitution of the seventh residue within the L12 linker domain. The valine at this position is absolutely conserved in all type II keratins, and in other intermediate filament subunits as well, which suggests that this residue makes an important contribution to filament integrity. Secondary structure analysis revealed that alanine at this position markedly reduces both the hydrophobicity and the beta-sheet nature of the L12 domain.
In affected members of a large French family with Dowling-Meara EBS (EBS2A; 619555), Rugg et al. (1999) identified a heterozygous G-to-A transition at the +1 position of the consensus GT donor splice site of intron 1 of KRT5. This mutation leads to the use of an exonic GT cryptic donor splice site located 66 nucleotides upstream from the normal donor splice site. The corresponding peptide deletion includes the last 5 amino acids of the H1 head domain and the first 17 amino acids of the conserved N-terminal end of the 1A rod domain, including the first 2 heptad repeats and the helix initiation peptide. Owing to the functional importance of the removed region, the data strongly suggested that shortened keratin polypeptide can impair keratin filament assembly in a dominant manner and cause the Dowling-Meara type of EBS.
In 5-year-old girl with no family history of skin disease who presented within hours of birth with extensive blistering of the skin and oral mucosa and subsequently developed hoarse cries, Shemanko et al. (2000) detected a heterozygous de novo T-to-C transition at the second nucleotide position of codon 181, resulting in a ser-to-pro amino acid change (ser181 to pro; S181P). The serine at position 181 in the helix initiation motif of keratin 5 is a highly conserved amino acid across keratins and other intermediate filament proteins. Although hoarseness is not a well documented feature of Dowling-Meara epidermolysis bullosa simplex (EBS2A; 619555), this patient and another (see 148066.0003) demonstrated that hoarseness does not necessarily indicate a poor prognosis.
Sprecher et al. (2003) reported a 25-year-old male of Ashkenazi Jewish origin whose initial clinical presentation, structural abnormalities of lesional skin, and course of disease were consistent with a very mild localized form of EBS (EBS2C; 619594). DNA sequence analysis of the complete coding sequence of the K5 gene disclosed in exon 9 a heterozygous guanine deletion at position 1635 downstream of the ATG start codon of K5 (1635delG). This mutation introduced a frameshift and delayed stop codon 80 amino acids downstream of the mutation site. The deletion was predicted to lead to the translation of an aberrant K5 protein carrying an elongated tail domain.
In a family diagnosed with epidermolysis bullosa simplex, Koebner type (EBS2B; 619588), Liovic et al. (2001) found a novel K5 mutation, val186 to leu (V186L), that produced a conservative amino acid change at position 18 of the 1A helix. The phenotype was unexpectedly severe for the location of the mutation, which lies outside the consensus helix initiation motif mutation hotspot, and other mutations at this position have been associated with Weber-Cockayne (mild) epidermolysis bullosa simplex (131800) only. De novo K5/K14 (148066) (mutant and wildtype) filament assembly in cultured cells was studied to determine the effect of this mutation on filament polymerization and stability. To visualize the structural impact of this mutation and to compare it with an analogous mutation causing mild disease, Liovic et al. (2001) generated a computer model of the 1A region of the K5/K14 coiled-coil. The results showed a high level of concordance between genetic, cell culture, and molecular modeling data, suggesting that even a conservative substitution can cause severe dysfunction in a structural protein, depending on the size and structure of the amino acid involved.
In a 38-year-old German woman with epidermolysis bullosa simplex, Dowling-Meara type (EBS2A; 619555) with severe palmoplantar keratoderma, Muller et al. (1999) found a heterozygous de novo 1429G-T transversion in the KRT5 gene that predicted a glu477-to-ter (E477X) substitution at the last glutamate residue of the KLLEGE motif. As a child, the patient developed severe palmoplantar hyperkeratoses before she began to walk. Her symptoms showed some improvement with age. The patient's unaffected parents, 2 sisters, and son did not carry the mutation.
Livingston et al. (2001) reported an epidermolysis bullosa simplex patient with severe palmoplantar keratosis, underlying erythema in a 'glove and moccasin' distribution, and limited range of motion in the fingers. Clinical, histologic, and ultrastructural features were consistent with a diagnosis of generalized EBS, Koebner subtype (EBS2B; 619588). The patient had a novel single-base substitution, 1414A-T, in the KRT5 gene that changed the lysine residue at amino acid 472 to a nonsense codon (K472X). This change predicted the synthesis of a truncated keratin-5, missing 119 amino acids, including the entire tail domain and the highly conserved KLLEGE motif at the carboxy terminus of the 2B domain of the central rod. Expression of an altered keratin-5, of predicted mass and pI for the product of the K472X allele, was documented by 1- and 2-dimensional Western blots of protein extracts from patient skin. Ultrastructural analysis of the patient's nonhyperkeratotic skin was remarkable for basal keratinocytes with dense and irregular keratin filaments proximal to the basement membrane. Keratinocytes, transfected with a cDNA carrying the K472X nonsense mutation, overexpressed a truncated keratin-5, and showed a disorganized and collapsed keratin filament cytoskeleton. This was the second epidermolysis bullosa simplex patient reported with a premature termination mutation in the KLLEGE motif (see 148040.0015). The occurrence of severe palmoplantar hyperkeratosis in both patients suggested that the keratin-5 tail domain may have important functions in palmoplantar tissues.
EBS with Migratory Circinate Erythema
In a Japanese girl with epidermolysis bullosa simplex with migratory circinate erythema (EBS2E; 609352) and in 3 affected members (a girl, her mother, and her maternal uncle) of an unrelated 3-generation Korean family, Gu et al. (2003) identified heterozygosity for a deletion mutation (1649delG) in exon 9 of the KRT5 gene, involving the V2 domain and predicted to cause a frameshift that would delay the termination codon and result in a protein 35 amino acids longer than the wildtype. The patients had a phenotype that was less severe than that of EBS Dowling-Meara, with an unusual migratory circinate erythema and multiple vesicles on the erythematous area. In both patients, the lesions healed without scarring but with brown pigmentation. The mother of the Korean girl had generalized hypopigmented and hyperpigmented patches on the trunk and extremities, but only occasional small vesicles in these same areas. All affected adults in this family had similar pigmentary changes. The mutation in the Japanese girl was assumed to have arisen de novo, as there were no other affected family members, and the mutation was not found in the DNA of blood samples from her parents.
When a younger sister with EBS was born into the Japanese family previously reported by Gu et al. (2003) and was found to have the same 1649delG mutation as her older sib, Nagao-Watanabe et al. (2004) reinvestigated the familial segregation of the mutation and identified heterozygosity for the deletion in the mother's DNA from hair bulb and buccal cell samples. Closer scrutiny of the mother's history revealed that she had migratory circinate pigmentation of the skin in childhood, and Nagao-Watanabe et al. (2004) concluded that this represented maternal somatic and germline mosaicism.
In a 3-year-old Japanese girl with EBS with migratory circinate erythema, Kumagai et al. (2017) identified heterozygosity for a de novo occurrence of the c.1649delG mutation in the KRT5 gene. The authors noted that the migratory circinate erythema appeared in infancy and spontaneously resolved, and the patient then developed mottled pigmentation.
EBS with Mottled Pigmentation
In 2 affected members of a Japanese family with epidermolysis bullosa simplex with mottled pigmentation (EBS2F; 131960), Horiguchi et al. (2005) detected heterozygosity for a 1-basepair deletion (c.1649delG) in exon 9 of the KRT5 gene resulting in replacement of the C-terminal domain of the protein with an aberrant sequence of 76 amino acids very rich in alanine and proline residues that is 35 amino acids longer than wildtype. Horiguchi et al. (2005) noted that this mutation had previously been identified in patients with EBS with migratory circinate erythema (EBS2E; 609352) by Gu et al. (2003).
In 2 Chinese sibs with EBS with mottled pigmentation (EBS2F) and in their affected mother, Tang et al. (2009) detected heterozygosity for the c.1649delG mutation in KRT5, resulting in frameshift and extension of the protein (Gly550AlafsTer77).
In an infant girl who exhibited EBS with mottled pigmentation (EBS2F; 131960), Geller et al. (2013) identified heterozygosity for the c.1649delG mutation in the KRT5 gene.
In 2 German pedigrees with Dowling-Degos disease (DDD1; 179850) described by Biltz and Kiessling (1988) and Milde et al. (1994), Betz et al. (2006) demonstrated a single adenine base insertion in the KRT5 gene (418dupA). The mutation was predicted to lead to frameshift and premature termination of translation at codon 178 (Ile140AsnfsTer39). Haplotype and SNP analyses revealed that the mutation arose on the same genetic background in the 2 families, suggesting a common ancestor. Betz et al. (2006) also performed mutation analysis on the KRT5 gene in 8 patients not belonging to the original pedigrees. In 5 of the 8 screened patients, the frameshift mutation was also identified. Genotyping of additional markers around the mutation showed a result compatible with the existence of a common ancestor for all affected individuals. Milde et al. (1994) described the disorder in the family they reported as Dowling-Degos-Kitamura disease.
In 5 unrelated patients with Dowling-Degos disease who also exhibited acantholysis on histopathology, Hanneken et al. (2010) identified heterozygosity for the 418dupA mutation; the duplication was also present in 4 clinically affected family members of 1 of the probands. Review of histopathologic findings in 3 DDD1 patients previously found to carry the 418dupA mutation in KRT5 by Betz et al. (2006) revealed acantholytic changes in biopsy specimens from all 3 patients.
In a patient with Dowling-Degos disease (DDD1; 179850) reported by Braun-Falco and Ring (2003), Betz et al. (2006) found a heterozygous nonsense mutation resulting in a premature stop codon (14C-A; S5X).
Yasukawa et al. (2002) described a Japanese family with EBS and 2 mutations in the KRT5 gene, resulting in phenotypic variability. Individuals with blisters localized to the palms and soles, who had received a diagnosis of EBS Weber-Cockayne type (EBS2C; 619594), were heterozygous for a G-to-A transition in exon 1, resulting in a glu170-to-lys (E170K) substitution in the highly conserved helix initiation peptide sequence of the 1A rod domain. One individual, with a classic phenotype of generalized blistering who had received a diagnosis of EBS Koebner type (see EBS2B, 619588), was compound heterozygous for the E170K mutation and a G-to-A transition in exon 7 of KRT5, resulting in a glu418-to-lys (E418K; 148040.0021) substitution in the 2B domain, which is the so-called 'stutter' region, an interruption in the heptad repeat substructure. Two unaffected family members were heterozygous for the E418K substitution, implying that it is not pathogenic in isolation. Neither mutation was identified in 100 control alleles. In vitro functional expression studies showed that cells transfected with either mutation developed small ball-like filament aggregates, indicating a disruption of the keratin network, although the effect was more pronounced for the E170K mutation. Expression of both mutant proteins exacerbated the clumping and resulted in significantly more disruption than either alone. These findings were consistent with the marked phenotypic and genotypic variability observed in this family.
Homozygosity for E170K
Oldak et al. (2011) reported a clinically heterogeneous EBS family with the E170K mutation in the KRT5 gene. The proband was a 10-year-old girl who had received a diagnosis of EBS Koebner type and had widespread blistering and skin fragility that improved with age. She was found to be homozygous for the E170K mutation. Each of her parents carried the E170K mutation in heterozygosity and had blisters restricted to soles of the feet since their teenage years after extensive walking; they were diagnosed with localized EBS. Oldak et al. (2011) concluded that the KRT5 E170K mutation alone causes a mild phenotype, and exhibits a gene dosage effect consistent with the phenomenon of 'partial dominance.' Oldak et al. (2011) noted that partial dominance had also been reported with the KRT14 mutation M119I (148066.0010).
The proband of the family reported by Gonzalez-Cantero et al. (2017) was a 7-year-old girl who had blisters and erosions from birth on palms, soles, and other trauma-prone sites. She was homozygous for the E170K mutation. Her parents, who were heterozygotes for the mutation, had a 'nail only' phenotype, with no blisters or erosions but mildly dystrophic toenails, micronychia and thickening of the nail plate of the second toe, and horizontal ridging of the great toenail. Gonzalez-Cantero et al. (2017) noted that the E170K mutation exhibits 'partial dominance.'
Vahidnezhad et al. (2019) reported a 32-year-old woman from a consanguineous family (family 1) of Iranian origin with Kurdish ethnicity who had trauma-induced blistering and erosions noted a few days after birth. She was homozygous for the E170K mutation. Although her parents, who were heterozygous for the mutation, were described as 'clinically unaffected,' they were noted to have mild blistering of the feet after strenuous and prolonged walking, and showed evidence of perturbed intermediate filament assembly in basal keratinocytes on electron microscopy.
In a Japanese man with epidermolysis bullosa simplex (EBS) that was more severe than that seen in other members of his family, Yasukawa et al. (2002) detected compound heterozygosity for an E170K mutation in KRT5 (148040.0020) and a glu418-to-lys (E418K) mutation, arising from a G-to-A transition in exon 7. The E418K substitution occurs in the 2B domain of keratin-5, which is the so-called 'stutter' region, an interruption in the heptad repeat substructure. Family members who carried the E418K mutation alone were unaffected, implying that it is not pathogenic in isolation. The E418K mutation was not found among 100 control individuals.
In a 2-year-old boy with severe autosomal recessive EBS (EBS2D; 619599), Tryon et al. (2019) detected homozygosity for a c.817delG deletion in the KRT5 gene that resulted in premature termination of the protein (val273-to-ter, V273X) in the 1B domain. The unaffected parents and brother were heterozygous for the mutation. Immunofluorescence staining of a full-thickness skin biopsy from the patient showed normal staining for collagens VII (see 120120) and XVII (113811) and laminins A3 (600805), B3 (150310), and C2 (150292). However, the epidermis was thin, with discontinuous sparse staining for keratin-5 and -14 (148066). Immunoelectron microscopy showed disorganization of cytoplasmic contents of basal keratinocytes and mostly absent intermediate filaments. The patient died at 26 months of age.
In a 4-year old boy (patient 2) with generalized skin blistering from birth (EBS2D; 619599), Vahidnezhad et al. (2019) detected homozygosity for a c.472G-A transition (c.472G-A, NM_000424.4) in the KRT5 gene that resulted in an asp158-to-asn substitution (D158N). Each unaffected parent was heterozygous for the mutation. The variant was not present in the ExAC, 1000 Genomes, or gnomAD databases. Keratin-5 and -14 (148066) staining in patient skin revealed irregular labeling.
In an infant girl (patient 3) with severe epidermolysis bullosa simplex (EBS2D; 619599) who died at 4 weeks of age, Vahidnezhad et al. (2019) identified homozygosity for a c.1440-1G-A transition (c.1440-1G-A, NM_000424.4) at the acceptor splice site of intron 7 of the KRT5 gene. Immunofluorescence staining of patient skin showed complete absence of keratin-5. The unaffected parents were heterozygous for the mutation, which was not found in the ExAC, 1000 Genomes, or gnomAD databases.
From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 7 patients (EBS2A; 619555) who were heterozygous for a c.1429G-A transition in exon 7 of the KRT5 gene, resulting in a glu477-to-lys (E477K) substitution at the second glutamate in the KLLEGE motif, which is the most evolutionarily conserved motif among all the intermediate filament proteins. Five of the children died in infancy. The E477K variant occurred de novo in 6 of the children; 1 of the deceased infants had an affected mother who also carried the variant. The authors noted that the E477K variant had been reported previously in 10 cases of generalized severe EBS, but clinical information was limited and mortality data were not reported. The authors suggested that the E477K variant might predispose to a severe and potentially lethal form of generalized severe EBS, noting that survivors were likely to be overrepresented if some affected neonates died before genetic studies were performed and the mutation occurred de novo.
Lalor et al. (2019) ascertained 6 children from national or local epidermolysis bullosa databases, from the United States, Italy, Germany, Finland, and Chile, in whom Sanger sequencing had revealed heterozygosity for c.1429G-A transition (c.1429G-A, NM_000424.3) resulting in an E477K substitution in the KRT5 gene. All were severely affected and 1 infant died. In 5 patients, the mutation was demonstrated to have arisen de novo; genetic analysis had not yet been performed in the parents of the sixth patient. The surviving children developed a distinctive reticulated skin pattern that the authors suggested might be pathognomonic; they noted that it was different from the pigmentation observed in EBS with mottled pigmentation (EBS2F; 131960).
In a 3-year-old Japanese boy (family 1) with EBS with migratory circinate erythema (EBS2E; 609352), Kumagai et al. (2017) identified heterozygosity for a 4-bp deletion (c.1638_1641delCATG) in the KRT5 gene, causing a frameshift predicted to result in deletion of the C-terminal 44 amino acids, with the addition of a frameshifted peptide of 78 residues. The authors noted that the C-terminal 76 amino acids were identical to the frameshifted peptide resulting from the recurrent c.1649delG mutation (148040.0017). The mutation was also found in his affected father and paternal grandmother. All affected individuals had migratory circinate erythema in infancy, but then developed mottled pigmentation.
In a 9-year-old Korean boy who had EBS with migratory circinate erythema (EBS2E; 609352), Lee et al. (2018) identified heterozygosity for a de novo in-frame 12-bp deletion (c.1321_1332del12) in exon 7 of the KRT5 gene, causing deletion of 3 amino acids (Lys441_Gln444del) from the 2B domain. The mutation was not found in his unaffected parents or in public variant databases. Unlike previously reported patients with EBS2E, the proband did not develop migratory circinate erythema until 9 years of age.
In a 2.5-year-old Turkish boy who had EBS with migratory circinate erythema (EBS2E; 609352), Yalici-Armagan et al. (2020) identified heterozygosity for a 1-bp deletion (c.1650delC) in exon 9 of the KRT5 gene, causing a frameshift predicted to result in a premature termination codon (Gly550Terfs). His affected mother was heterozygous for the mutation, which was not found in public variant databases. He was also heterozygous for a D197E substitution in KRT5, for which his unaffected father was homozygous; this variant was believed to be nonpathogenic.
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