Alternative titles; symbols
HGNC Approved Gene Symbol: KRT10
SNOMEDCT: 1255143006, 703504006, 718631006;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:40,818,117-40,822,614 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | ?Ichthyosis histrix, Lambert type | 146600 | Autosomal dominant | 3 |
| Epidermolytic hyperkeratosis 2A, autosomal dominant | 620150 | Autosomal dominant | 3 | |
| Epidermolytic hyperkeratosis 2B, autosomal recessive | 620707 | Autosomal recessive | 3 | |
| Ichthyosis with confetti | 609165 | Autosomal dominant | 3 | |
| Ichthyosis, annular epidermolytic 1 | 607602 | Autosomal dominant | 3 |
The KRT10 gene encodes keratin-10, an intermediate filament (IF) chain which belongs to the acidic type I family and is expressed in terminally differentiated epidermal cells. Epithelial cells almost always coexpress pairs of type I and type II keratins, and the pairs that are coexpressed are highly characteristic of a given epithelial tissue. Suprabasal terminally differentiating cells express keratin-1 (KRT1; 139350) (type II) and KRT10 (type I).
Darmon et al. (1987) presented the nucleotide sequence of a 1,700 bp cDNA encoding human epidermal keratin-10 (56.5 kD). Zhou et al. (1988) presented the complete amino acid sequence of human keratin-10. Korge et al. (1992) described extensive polymorphism of the KRT10 gene, restricted to insertions and deletions of the glycine-rich quasipeptide repeats that form the glycine-loop motif in the C-terminal domain.
Langbein et al. (2005) examined the expression of several keratins in eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT10 was expressed throughout the duct region but not in the deeper secretory portion of the gland. In plantar epidermis, KRT10 was expressed in the stratum corneum through to the lower suprabasal layer, but not in the basal layer.
By use of specific cDNA clones in conjunction with somatic cell hybrid analysis and in situ hybridization, Lessin et al. (1988) mapped the KRT10 gene to 17q12-q21 in a region proximal to the breakpoint at 17q21 that is involved in a t(17;21)(q21;q22) translocation associated with a form of acute leukemia. KRT10 appeared to be telomeric to 3 other loci that map in the same region: CSF3 (138970), ERBA1 (190120), and HER2 (164870). NGFR (162010) and HOX2 (142960) are distal to K9. Romano et al. (1991) demonstrated that the KRT10, KRT13, and KRT15 genes are located in the same large pulsed field gel electrophoresis fragment. A correlation of assignments of the 3 genes makes 17q21-q22 the likely location of the cluster.
Autosomal Dominant Epidermolytic Hyperkeratosis 2A
Rothnagel et al. (1992), Cheng et al. (1992), and Chipev et al. (1994) described heterozygous mutations in the KRT10 gene (148080.0001-148080.0009) as the cause of epidermolytic hyperkeratosis (EHK2A; 620150). Heterozygous mutations in the KRT1 gene (139350) also cause EHK (see EHK1, 113800), a finding consistent with the fact that this keratin pair forms heterodimers and comprises the keratin intermediate filaments in the suprabasal epidermal cells.
Autosomal Recessive Epidermolytic Hyperkeratosis 2B
In a consanguineous family segregating autosomal recessive EHK (EHK2B; 620707), Muller et al. (2006) identified homozygosity for a nonsense mutation in the KRT10 gene (Q434X; 148080.0019) in 2 affected sibs. The clinically unaffected parents and 5 other unaffected relatives were heterozygous for the mutation, which was not found in 50 controls. Semiquantitative RT-PCR and Western blot analysis demonstrated degradation of the KRT10 transcript, resulting in complete absence of keratin-10 protein in the epidermis and cultured keratinocytes of the homozygous individuals. Muller et al. (2006) noted strong induction of the wound-healing keratins KRT6 (see 148041), KRT16 (148067), and KRT17 (148069) in the suprabasal dermis, which was unable to compensate for lack of KRT10.
In a 3-year-old Turkish girl with mild EHK, born of first-cousin parents, Tsubota et al. (2008) identified homozygosity for a nonsense mutation in the KRT10 gene (C427X; 148080.0020). Immunohistochemical labeling of suprabasal epidermal layers by antibodies to KRT5 (148040), KRT6, and KRT14 (148066) suggested compensatory expression of 1 or more of these keratins by suprabasal keratinocytes.
In a girl with severe EHK from a consanguineous family of Sudanese descent, Terheyden et al. (2009) identified homozygosity for a 1-bp insertion in the KRT10 gene (148080.0021). KRT6, KRT16, and KRT17 were upregulated in the proband, with maximal expression at the sites of cytolysis. Terheyden et al. (2009) noted that the 3 mutations reported to that time in recessive EHK were all located in exon 6 of the KRT10 gene, near the end of the 2B domain and just upstream of the highly conserved helix termination peptide.
In an infant with severe epidermolytic ichthyosis who was born of consanguineous North African parents and died at 3 days of age, Covaciu et al. (2010) identified homozygosity for a splice site mutation in the KRT10 gene (148080.0022). Immunohistology of the patient's skin showed loss of keratin-10 expression in the suprabasal epidermis, with induction of KRT5, KRT14, KRT16, and KRT17. The authors stated that their study confirmed that in humans, the compensatory upregulation of other cytokeratins in the suprabasal layers elicited by complete absence of KRT10 is not sufficient for phenotypic rescue.
Ichthyosis with Confetti
In 7 kindreds with ichthyosis with confetti (IWC; 609165), also known as congenital reticular ichthyosiform erythroderma (CRIE), Choate et al. (2010) identified heterozygous mutations in the KRT10 gene (see, e.g., 148080.0016-148080.0018) resulting in frameshifts that create an arginine-rich C terminus that redirects keratin-10 from the cytokeratin filament network to the nucleolus. None of the mutations were found in control chromosomes or in the revertant spots (clones of normal skin that arise from loss of heterozygosity on chromosome 17q via mitotic recombination) that comprise the 'confetti' for which the disorder is named.
In 6 probands with IWC and the affected monozygotic twin of 1 of the probands, Spoerri et al. (2015) sequenced the KRT10 gene and identified heterozygous frameshift mutations (see, e.g., c.1374-1G-C, 148080.0023), all of which were predicted to result in mutant proteins with an arginine-rich C terminus.
In a 28-year-old Caucasian man (IWC100) with IWC, Lim et al. (2016) sequenced the KRT10 gene and identified a de novo heterozygous 1-bp deletion (148080.0024), causing a frameshift predicted to replace the endogenous glycine-rich tail domain of keratin-10 with an alanine-rich motif that extends the C terminus by 19 additional amino acids. Laser capture microdissection of patient white spots revealed that each revertant spot harbored copy-neutral loss of heterozygosity in the proximal q arm of chromosome 17 extending to the telomere, consistent with reversion via mitotic recombination. However, Renz et al. (2019) analyzed the 1-bp deletion in patient IWC100 and demonstrated that the variant leads to several alternative splicing products, the majority of which result in an arginine-rich C terminus.
In a 7-month-old boy with IWC, Saito et al. (2017) identified heterozygosity for the recurrent KRT10 c.1374-1G-C splicing mutation (148080.0023), which had previously been reported in 3 patients with IWC.
In 2 unrelated patients with IWC, who both died from aggressive squamous cell carcinomas, Burger et al. (2020) identified heterozygosity for KRT10 mutations: the woman had the recurrent splicing mutation in intron 6 (148080.0023), and the man had an indel mutation in exon 7 (148080.0025).
Renz et al. (2019) noted that the genodermatosis IWC is caused by dominant-negative variants that result in aberrant KRT10 proteins that localize to the nucleus rather than the cytoplasm. The mislocalization is associated with a C terminus that is altered from a polyglycine tail to either a polyarginine or polyalanine tail. Renz et al. (2019) demonstrated that only K10 with an arginine-rich C terminus (K10arg) translocates to the nucleus, whereas wildtype K10, K10ala, and truncated K10 remain in the cytoplasm. The authors also showed that the presence of K10arg enables cotranslocation of non-K10arg proteins into the nucleus. They concluded that arginine-rich K10 tails are responsible for the pathogenic nuclear localization of K10 in patients with IWC.
Nonepidermolytic Keratosis Palmaris et Plantaris
In a 5-generation Uzbek family with nonepidermolytic keratosis palmaris et plantaris (NEPPK; 600962), Rogaev et al. (1993) found tight linkage to an insertion-deletion polymorphism in the C-terminal coding region of the KRT10 gene (maximum lod score = 8.36 at theta = 0.00). It is noteworthy that it was a rare, high molecular weight allele of the KRT10 polymorphism that segregated with the disorder. The allele was observed once in 96 independent chromosomes from unaffected Caucasians. The KRT10 polymorphism arose from the insertion/deletion of imperfect (CCG)n repeats within the coding region and gave rise to a variable glycine loop motif in the C-terminal tail of the keratin-10 protein. It is possible that there was a pathogenic role for the expansion of the imperfect trinucleotide repeat.
Annular Epidermolytic Ichthyosis 1
In a father and daughter who had annular epidermolytic ichthyosis (AEI1; 607602), Joh et al. (1997) identified a heterozygous missense mutation in the KRT10 gene (R83E; 148080.0014) that segregated with disease in the family and was not found in controls.
In a mother and her 2 children with AEI, Suga et al. (1998) screened the KRT1, KRT2, and KRT10 genes and identified heterozygosity for a missense mutation in the KRT10 gene (I107T; 148080.0028). The mutation was not found in unaffected family members or in 50 controls.
Ichthyosis Hystrix, Lambert Type
In a 3-generation Chinese family with ichthyosis hystrix of the Lambert type (IHL; 146600), Wang et al. (2016) performed whole-exome sequencing and identified a heterozygous missense mutation in the KRT10 gene (L435P; 148080.0026) that segregated fully with disease and was not found in 100 ethnically matched controls. The mutation was located very close to the tail domain of KRT10; noting that all previously reported mutations associated with ichthyosis hystrix of the Curth-Macklin type (IHCM; 146590) were frameshifts involving the tail domain of the KRT1 gene, the authors hypothesized a genotype/phenotype correlation in which mutation in or close to the tail domain of the KRT1/KRT10 genes causes ichthyosis hystrix, with perinuclear shells ultrastructurally and no clinical blistering, whereas mutation in the rod domain causes a defect resulting in clumps of tonofibrils surrounding the nucleus ultrastructurally and blister formation clinically, as in epidermolytic ichthyosis.
Associations Pending Confirmation
For discussion of a possible association between variation in the KRT10 gene and ichthyosis hystrix of the Curth-Macklin type (IHCM; 146590), see 148080.0027.
Fuchs et al. (1992) discovered that transgenic mice expressing a mutant keratin-10 gene have the phenotype of epidermolytic hyperkeratosis (EHK; 113800), thus suggesting that a genetic basis for the human disorder resides in mutations in genes encoding suprabasal keratins KRT1 (139350) or KRT10. They also showed that stimulation of basal cell proliferation can result from a defect in suprabasal cells and that distortion of nuclear shape or aberrations in cytokinesis can occur when an intermediate filament network is perturbed.
In a 17-year-old girl (WL) with epidermolytic hyperkeratosis (EHK2A; 620150), Rothnagel et al. (1992) demonstrated heterozygosity for an arg10-to-his (R10H) mutation due to a G-to-A transition in the KRT10 gene. The patient still exhibited frequent blistering in addition to hyperkeratotic lesions on his limbs, trunk, and face.
Rothnagel et al. (1993) identified a heterozygous R10H mutation in a 4-generation family (EHK-E/S) and an individual (EHK-A) with EHK.
Chipev et al. (1994) found the arg10-to-his mutation in 2 families (1014 and 1024) with epidermolytic hyperkeratosis.
In a mother and son (family EHK-O) with epidermolytic hyperkeratosis (EHK2A; 620150), Rothnagel et al. (1992) demonstrated a T-to-C transition in codon 15 of the KRT10 gene resulting in substitution of serine for leucine (L15S) in the keratin-10 protein. Both affected persons showed widespread hyperkeratosis and palmoplantar keratoderma.
In 2 (EH4 and EH6) of 6 unrelated cases of epidermolytic hyperkeratosis (EHK2A; 620150), Cheng et al. (1992) found a heterozygous CGC-to-CAC transition at codon 156 of the KRT10 gene resulting in substitution of histidine for arginine (R156H). By genetic engineering, gene transfection, and 10-nm filament assembly, Cheng et al. (1992) demonstrated that this mutation is functionally responsible for the keratin filament clumping that occurs in basal cells in epidermolysis bullosa simplex and suprabasal cells in EHK. An explanation may be provided for the seemingly binucleate cells typical of EHK. They commented on the fact that the arg156-to-his mutation of the KRT10 gene in the EHK patients is in exactly the same position of the rod as the arg125-to-his mutation of the KRT14 gene leading to Dowling-Meara epidermolysis bullosa simplex (148066.0003).
In a family (EH6) with EHK in which Cheng et al. (1992) had identified an R156H mutation in the KRT10 gene, Paller et al. (1994) found that blood genomic DNA from the grandmother, who had markedly milder EHK and extensive epidermal nevi, showed underrepresentation of the mutation. From these findings, Paller et al. (1994) reasoned that the epidermolytic hyperkeratotic form of epidermal nevus arises from a postzygotic KRT1 or KRT10 mutation in a cell destined to become an epidermal keratinocyte. They showed that 50% of the KRT10 alleles of epidermal cells carried the point mutation in keratinocytes from lesional skin of the grandmother, whereas no mutations were detected in normal skin. The mutation was present in 50% of the KRT10 alleles from all cell types examined in her daughter and granddaughter, both of whom had generalized epidermolytic hyperkeratosis.
In an individual (EHK-K) with epidermolytic hyperkeratosis (EHK2A; 620150), Rothnagel et al. (1993) identified a heterozygous C-to-T transition in the KRT10 gene resulting in an arg10-to-cys (R10C) substitution. Rothnagel et al. (1993) concluded that there is a mutation hotspot within the 1A alpha-helical segment of KRT10 responsible for EHK. Mutations at residue 10 of the rod domain involved arginine to histidine (148080.0001), arginine to cysteine, and arginine to leucine (148080.0005). (It should be noted that arginine-125 in the KRT14 gene seems to be a similar mutation hotspot; in that case, epidermolysis bullosa simplex results from mutation in arginine-125 to histidine, cysteine, or leucine.)
In a family (1013) with epidermolytic hyperkeratosis, Chipev et al. (1994) also identified an arg10-to-cys mutation in the beginning of the 1A rod domain of keratin-10.
In an individual (EHK-D) with epidermolytic hyperkeratosis (EHK2A; 620150), Rothnagel et al. (1993) identified a heterozygous G-to-T transversion in the KRT10 gene that resulted in an arg10-to-leu (R10L) amino acid substitution.
In a 43-year-old woman (1001) with epidermolytic hyperkeratosis (EHK2A; 620150), Chipev et al. (1994) identified a heterozygous A-to-C transversion in the KRT10 gene that resulted in an asn8-to-his mutation (N8H) in the beginning of the 1A rod domain of keratin-10. The mutation was not present in either of her unaffected parents.
In a 32-year-old woman (1008) with epidermolytic hyperkeratosis (EHK2A; 620150), Chipev et al. (1994) identified a heterozygous T-to-G transversion in the KRT10 gene, resulting in a tyr14-to-asp (Y14D) mutation in the beginning of the rod domain 1A of keratin-10. The mutation was not present in either of her unaffected parents or in 42 control individuals.
In 3 affected members in 3 generations of a family (1006) with epidermolytic hyperkeratosis (EHK2A; 620150), Chipev et al. (1994) identified a heterozygous T-to-A transversion in the KRT10 gene that resulted in a leu103-to-gln (L103Q) mutation in the conserved region late in the 2B rod domain of keratin-10.
In 2 unrelated individuals (EH3 and EH13) with severe epidermolytic hyperkeratosis (EHK2A; 620150) Syder et al. (1994) found a heterozygous C-to-T transition at nucleotide 466 in exon 1 of the KRT10 gene, resulting in an arg156-to-cys (R156C) mutation in keratin-10. The arginine at this position is conserved and had previously been shown to be mutated to a histidine (148080.0003) in 2 unrelated EHK families.
Paller et al. (1994) studied a woman (B1) with epidermal nevi who had a daughter (B2) with epidermolytic hyperkeratosis. In the mother, 50% of the KRT10 alleles carried the arg156-to-cys mutation in lesional skin, whereas the mutation was not detected in normal skin. In the case of the daughter, the mutation was present in 50% of the KRT10 alleles from all cell types examined. These patients had been reported by Nazzaro et al. (1990).
In an individual (EH2) with severe epidermolytic hyperkeratosis (EHK2A; 620150) Syder et al. (1994) found a heterozygous T-to-G transversion in the KRT10 gene that resulted in a methionine-to-arginine substitution at codon 150 (M150R). This mutation was 6 residues from the site of the R156H (148080.0003) and R156C (148080.0010) mutations which were also associated with severe epidermolysis bullosa. All are within the amino end of the alpha-helical rod domain of KRT10. In contrast, affected members of an atypically mild family had a mutation just proximal to the conserved carboxy end of the KRT10 rod (148080.0012). By genetic engineering and gene transfection, Syder et al. (1994) demonstrated that each mutation was functionally responsible for the keratin filament aberrations that were typical of keratinocytes cultured from the patients. Moreover, they showed that the mild EHK mutation affected filament network formation less severely.
In affected members of a family (EH7) with atypically mild epidermolytic hyperkeratosis (EHK2A; 113800), Syder et al. (1994) found a heterozygous A-to-G transition at nucleotide 1315 of the KRT10 gene, resulting in a lys439-to-glu (K439E) mutation located just proximal to the conserved carboxy end of the KRT10 rod. The location of the mutation was thought to account for the fact that clinical manifestations were mild compared with those in families with mutations in the amino end of the alpha-helical rod domain of KRT10 (e.g., 148080.0011). In general, epidermolytic hyperkeratosis shows marked clinical heterogeneity with respect to severity of blistering, keratoderma, and erythroderma, and with respect to the extent of body involvement. In family EH7, affected individuals did not have clinical signs until around 2 years of age. Manifestations then became more severe during childhood but significantly improved by adulthood.
In a boy (A-2) with epidermolytic hyperkeratosis (EHK2A; 620150), Paller et al. (1994) identified a heterozygous c.449T-C transition in the KRT10 gene that resulted in substitution of thr for met150 (M150T) at the conserved N-terminal end of the rod segment of K10. The boy and his father had been reported by Nazzaro et al. (1990) as family 2, one of 2 families in their report in which the generalized form of epidermolytic hyperkeratosis was observed in children of parents with the linear form of EHK. Paller et al. (1994) found that the mutation was absent or underrepresented in blood and skin fibroblasts of the parent with the nevus, was present in 50% of the KRT10 alleles of keratinocytes from lesional skin, and was absent in normal skin. In a second family of this type, they found an arg156-to-cys mutation (R156C; 148080.0010), and in a third family, they found an arg156-to-his mutation (R156H; 148080.0003).
In a father and daughter who had annular epidermolytic ichthyosis (AEI1; 607602), Joh et al. (1997) identified heterozygosity for a tandem CG-to-GA mutation in the KRT10 gene, resulting in an arg83-to-glu (R83E) substitution at a highly conserved residue within the 2B helical segment. The mutation segregated fully with disease in the family, and was not found in 50 unrelated controls.
In a patient with ichthyosis with confetti (IWC; 609165), Choate et al. (2010) identified a heterozygous splice site mutation in the intron 6 splice acceptor site of the KRT10 gene. The mutation created a new splice acceptor site leading to an 8-bp deletion resulting in frameshift (Ser458ArgfsTer120). This mutation generated a protein with an arginine-rich C terminus that redirected keratin-10 from the cytokeratin filament network to the nucleolus. This mutation was not identified in this patient's parents or in control chromosomes. Two similar mutations affecting the intron 6 splice acceptor were identified in 2 other de novo cases.
In a mother and 2 of her offspring, all affected with ichthyosis with confetti (IWC; 609165), Choate et al. (2010) identified a G-to-A transition at the +1 position of the intron 6 splice donor site of KRT10. The mutation resulted in skipping of exon 6 with a junction between exons 5 and 7 (delK386-S458, Gly459PhefsTer122). This mutation generated a protein with an arginine-rich C terminus that redirected keratin-10 from the cytokeratin filament network to the nucleolus.
In a patient with de novo ichthyosis with confetti (IWC; 609165), Choate et al. (2010) identified a single-basepair insertion at position 1450 in exon 7 of the KRT10 gene that resulted in a frameshift at codon 484 (Gly484ArgfsTer97). This mutation generated a protein with an arginine-rich C terminus that redirected keratin-10 from the cytokeratin filament network to the nucleolus.
In a father and daughter with ichthyosis with confetti (IWC; 609165), Choate et al. (2010) identified a 2-bp deletion at position 1560 in exon 7 of the KRT10 gene resulting in a frameshift at codon 521 (Gly521ProfsTer59). This mutation generated a protein with an arginine-rich C terminus that redirected keratin-10 from the cytokeratin filament network to the nucleolus.
In a brother and sister with epidermolytic hyperkeratosis (EHK2B; 620707), born of first-cousin parents, Muller et al. (2006) identified homozygosity for a c.1300C-T transition in exon 6 of the KRT10 gene, resulting in a gln434-to-ter (Q434X) substitution causing a premature termination codon 25 amino acids prior to the end of the 2B domain of keratin-10. The unaffected parents, 2 unaffected sibs, and 3 other unaffected relatives were heterozygous for the mutation, which was not found in 50 controls. Semiquantitative RT-PCR of RNA from cultured keratinocytes indicated massive reduction of specific KRT10 mRNA levels in the homozygous children, and immunofluorescence and Western blot analysis demonstrated complete absence of keratin-10 protein in their epidermis and keratinocytes, respectively. The results indicated that the mutation led to instability and degradation of the mutant transcript, and the homozygous patients represented a complete human knockout of the KRT10 gene.
In a 3-year-old Turkish girl with mild epidermolytic hyperkeratosis (EHK2B; 620707), born of first-cousin parents, Tsubota et al. (2008) identified homozygosity for a 2-bp transversion (c.1281_1282CC-AA) in exon 6 of the KRT10 gene, resulting in a cys427-to-ter (C427X) substitution causing a premature termination codon 34 amino acids prior to the end of the 2B domain of keratin-10. The unaffected parents were heterozygous carriers of the mutation, which was not found in 50 controls. Immunohistochemical analysis demonstrated complete lack of keratin-10 protein in the patient's epidermis. Tsubota et al. (2008) hypothesized that the mutant transcript was targeted by nonsense-mediated decay (NMD).
In a girl with severe epidermolytic hyperkeratosis (EHK2B; 620707) from a consanguineous family of Sudanese descent, Terheyden et al. (2009) identified homozygosity for a 1-bp insertion (c.1325insC) in exon 6 of the KRT10 gene, causing a frameshift that resulted in a premature termination codon 6 amino acids downstream (Lys439fsTer6) in the 2B domain of keratin-10. Her unaffected parents and brother were heterozygous carriers of the mutation, which was not found in 50 controls. Quantitative RT-PCR showed a significant decrease of specific KRT10 mRNA in the skin of the patient, whereas levels in the heterozygous father were approximately 50% of wildtype. The findings confirmed that the mutant transcript was degraded by nonsense-mediated decay (NMD).
In an infant with severe epidermolytic hyperkeratosis (EHK2B; 620707), born of consanguineous North African parents, Covaciu et al. (2010) identified homozygosity for a G-A transition (1155+5G-A, NM_000421.3) in intron 5 of the KRT10 gene. The unaffected parents were heterozygous for the mutation. RT-PCR analysis of total RNA from the patient's cultured keratinocytes revealed that the splice site mutation results in a premature termination codon that truncates KRT10 in the proximal portion of the 2B helical domain. Immunohistology of the patient's skin showed loss of keratin-10 expression in the suprabasal epidermis. Covaciu et al. (2010) stated that the mutation caused degradation of the transcript by nonsense-mediated mRNA decay (NMD). The infant became septic with hypernatremic dehydration soon after birth and died at 3 days of age.
In a young adult man (patient 2) with ichthyosis with confetti (IWC; 609165), Spoerri et al. (2015) identified heterozygosity for a de novo splicing mutation (c.1374-1G-C) in intron 6 of the KRT10 gene, predicted to cause a frameshift resulting in a premature termination codon (Ser458ArgfsTer120). The patient was born with a collodion membrane and exhibited other ectodermal anomalies including small malformed ears, hypoplastic nipples, and dorsal acral hypertrichosis, as well as eyelid ectropion, scant eyebrows and eyelashes, and large lunulae with long nail plates. Hyperpigmentation was noted within areas of healthy (revertant) skin.
In a 7-month-old boy with IWC, Saito et al. (2017) identified a de novo heterozygous c.1374-1G-C splicing mutation in the KRT10 gene, which they noted was a recurrent variant that had previously been reported in 3 patients with IWC. The proband had focal palmoplantar hyperkeratosis, which improved over time, as well as transient and nonrecurrent hyperpigmented warty keratotic papules in the flexures.
In a woman with IWC who died at age 36 years from aggressive squamous cell carcinoma, Burger et al. (2020) identified heterozygosity for the KRT10 c.1374-1G-C splicing mutation. The variant was not found in the gnomAD database. The patient was originally described with micropinnae, alopecia universalis and ectropion (MAUIE syndrome) by Hendrix et al. (1997).
In a 28-year-old man (IWC100) with ichthyosis with confetti (IWC; 609165), Lim et al. (2016) identified heterozygosity for a de novo 1-bp deletion (c.1373delG) at the last base of exon 6 of the KRT10 gene, causing a frameshift that replaced the endogenous glycine-rich tail domain of keratin-10 with an alanine-rich motif that extended the C terminus by 19 additional amino acids. Immunolocalization in affected skin showed an overall reduction in suprabasal K10 staining, with evidence of filament network collapse and focal aggregates within the nucleus; these findings were not seen in revertant or normal control skin. Costaining with a nucleolar marker revealed K10 aggregates within the nucleolus. Immunolocalization of the KRT10 binding partner KRT1 (139350) also demonstrated nuclear mislocalization. Laser-capture microdissection of 3 white spots revealed that each revertant spot harbored copy-neutral loss of heterozygosity in the proximal q arm of chromosome 17 extending to the telomere, consistent with reversion via mitotic recombination. For all 3 revertant spots, the region of crossover was estimated to fall between SNPs rs6505079 and rs8078229.
Renz et al. (2019) stated that the correct designation for this mutation is c.1373+1delG. Analysis of NKc21 keratinocytes transfected with the variant from patient IWC100 revealed 5 different splicing products, including 3 that encoded K10 with an arginine tail (K10arg), 1 that encoded a truncated K10 protein, and a minor transcript encoding K10 with an alanine tail (K10ala). Immunofluorescence analysis demonstrated aberrant nuclear localization of K10arg but not of K10ala; however, the presence of K10arg was shown to enable cotranslocation of non-K10arg, including wildtype or truncated K10, into the nucleus. The authors concluded that arginine-rich, rather than alanine-rich, K10 tails are responsible for the pathogenic nuclear localization of K10 in patients with IWC.
In a man with ichthyosis with confetti (IWC; 609165), who also had micropinnae, alopecia universalis, and ectropion, Burger et al. (2020) identified heterozygosity for an insertion/deletion mutation (c.1403_1417delinsA) in exon 7 of the KRT10 gene, causing a frameshift predicted to result in a premature termination codon (Ser468LysfsTer108). The mutation was not found in the gnomAD database. The patient, who was originally reported by Elbaum et al. (1995), died at age 23 from aggressive squamous cell carcinoma.
In a Chinese mother and her son and daughter with ichthyosis hystrix of the Lambert type (IHL; 146600), originally described by Wang et al. (2007), Wang et al. (2016) performed whole-exome sequencing and identified heterozygosity for a c.1304T-C transition in exon 6 of the KRT10 gene, resulting in a leu435-to-pro (L435P) substitution at a conserved residue within a helix in the 2B rod domain, adjacent to the tail domain. The mutation was confirmed by Sanger sequencing and was not found in 5 unaffected family members or in 100 ethnically matched controls.
This variant is classified as a variant of unknown significance because its contribution to ichthyosis hystrix, Curth-Macklin type (IHCM; 146590) has not been confirmed.
In a female patient with ichthyosis hystrix of the Curth-Macklin type, who was negative for mutation in the KRT1 gene (139350), Terrinoni et al. (2018) identified heterozygosity for a de novo 3-bp deletion (c.1334_1336delAAT) in exon 6 of the KRT10 gene, involving the last base of codon 445 and the first 2 bases of codon 446, thus resulting in substitution of glu445 and ile446 by an asp residue (Glu445_Ile446delinsAsp) with reversion of the sequence to frame. The mutation was predicted to cause a rotational change, altering the pairing of all subsequent amino acids and impairing the correct interaction between the V2 domains of K1 and K10. The proband was born with diffuse erythrodermic hyperkeratosis, and by the age of 13 months she exhibited intense widespread hyperkeratosis with a papillomatous appearance, with sparing of only a few areas of the face. Later evaluation showed marked involvement of the extensor surfaces of the limbs and dorsal hands, and the palmoplantar surfaces were also affected. The dermatitis was pruritic; there was no blistering. Histologic examination of patient skin showed marked acanthosis, with a more than 20-fold expansion of the spinous layer, significant orthokeratotic hyperkeratosis, and focal parakeratotic cells, as well as intracytoplasmic vacuolization of the granular layer cells. Confocal analysis showed abnormal expression of K10 compared to control, with expansion of the basal cell layer and persistence of K14 (KRT14; 148066) in the upper layers as well as some overlap with K10 expression. Ultrastructural analysis revealed keratin filament shells in the cytoplasm around the nucleus, and several binuclear keratinocytes were observed in the granular layer. The authors stated that these findings, particularly the presence of binucleated cells and epidermolytic palmoplantar keratoderma, were consistent with a diagnosis of IHCM. No other family member had skin disease, and the deletion was not found in her unaffected parents, 50 unrelated control individuals, or the dbSNP database.
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