Alternative titles; symbols
HGNC Approved Gene Symbol: KRT16
SNOMEDCT: 39427000;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,609,778-41,612,767 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Pachyonychia congenita 1 | 167200 | Autosomal dominant | 3 |
| Palmoplantar keratoderma, nonepidermolytic, focal | 613000 | Autosomal dominant | 3 |
KRT16 belongs to a large group of acidic type I keratins that interact with basic type II keratins to form the 8-nm cytoskeletal filaments of epithelial cells. Both type I and type II keratins have a central alpha-helical domain of over 300 amino acids that mediates keratin interaction. KRT16 is constitutively expressed in most stratified squamous epithelia, but it is only transiently expressed in epidermis during hyperproliferation (summary by Albers and Fuchs (1987) and Rosenberg et al. (1988)).
Rosenberg et al. (1988) obtained a genomic clone containing the human K16 gene. The predicted 472-amino acid K16 protein contains a large alpha-helical domain. Northern blot analysis detected a 1.6-kb K16 transcript in cultured human epidermal cells and in a squamous cell carcinoma cell line. K16 had an apparent molecular mass of 48 kD by SDS-PAGE.
Paladini et al. (1995) cloned keratin-16 by applying RT-PCR on total RNA extracted from cultured primary human epidermal keratinocytes. The KRT16 cDNA encodes a deduced 473-amino acid protein with a calculated molecular mass of 48 kD. The protein shares strong sequence homology with the type I keratins KRT14 (148066) and KRT17 (148069).
Langbein et al. (2005) examined the expression of several keratins in eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT16 was expressed throughout the duct region and also in the deeper secretory portion of the gland. In plantar epidermis, KRT16 was expressed only in the basal layer and in the lower suprabasal layer.
Rosenberg et al. (1988) determined that the KRT16 gene contains 8 exons.
Rosenberg et al. (1988) mapped the KRT16 gene to chromosome 17. Rosenberg et al. (1991) stated that the KRT14 and KRT16 genes, as well as a yet-uncharacterized keratin gene, had been localized to chromosome 17q12-q21. Another cluster of genes located at chromosome 17p12-p11 contains a nonfunctional gene for KRT16 and 2 genes for KRT14, at least 1 of which is a pseudogene.
In a sporadic case of the Jadassohn-Lewandowsky type of pachyonychia congenita (PC1; 167200), McLean et al. (1995) identified heterozygosity for a leu132-to-pro mutation (148067.0001) in the helix initiation peptide of keratin-16.
The helix initiation motif (HIM) of KRT16 is a short sequence of about 20 amino acids at the start of the central alpha-helical rod domain whose sequence is conserved in all type I or acidic keratins. Most strongly dominant-negative mutations in keratins have been found to be missense (or occasionally in-frame deletion) mutations in this sequence or the equivalent sequence at the end of the rod domain, the helix termination motif (McLean, 1997). The helix initiation motif of KRT16 is KVTMQNLNDRLASYLDKA. It is the practice of keratin researchers to refer to mutations by the number of the amino acid affected in the helix 1A domain. Thus, the first mutation to be identified (148067.0001) can alternatively be designated leu132-to-pro or leu15-to-pro.
Shamsher et al. (1995) identified mutations in the helix initiation domain of the KRT16 gene (148067.0002-148067.0003) in 2 unrelated families with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000). These mutations did not appear to cause epidermolysis on light or electron microscopy, which may reflect differences in function, assembly, or interaction of the 'hyperproliferative' or 'mucoregenerative' keratins from other major types of keratins.
McLean (1997) pointed out that 2 families studied by Shamsher et al. (1995) had mild nail changes similar to those that occur in a much more severe form in pachyonychia congenita. McLean (1997) concluded that expression of the nail dystrophy in addition to the palmoplantar keratoderma is not dependent on the specific mutation, as this has been found to vary greatly within large families. Phenotype seems to vary greatly in all keratin diseases, even among persons with the same mutation, so there are probably modifier genes and/or environmental influences yet to be defined.
In a father and son with classic PC1 and a 3-generation family with mild focal NEPPK, Smith et al. (2000) identified a heterozygous mutation (L124R; 148067.0007) and a complex deletion (148067.0011) in the KRT16 gene, respectively. The authors noted that the deletion, which removes a K16 helix termination motif, unexpectedly resulted in a relatively mild phenotype. Studies in cultured epithelial cells demonstrated morphologic differences in the K16 aggregates produced by the missense and the deletion mutations; in addition, the L124R mutation appeared to cause complete collapse of the endogenous filament network, whereas some residual filamentous keratin was seen in cells expressing the deletion, implying that the deleted K16 may be less capable of disrupting keratin filaments by dominant-negative interference compared to the L124R mutation.
In a patient with unilateral palmoplantar verrucous nevus, Terrinoni et al. (2000) reported somatic mosaicism for a 12-bp deletion in the KRT16 gene in a biopsy from lesional epidermis. The patient had localized thickening of the skin in parts of the right palm and the right sole, following the Blaschko lines (see 613000).
Smith et al. (2005) identified keratin mutations in 30 probands from the International Pachyonychia Congenita Research Registry, including 8 patients with mutations in the KRT16 gene (see, e.g., 148067.0001-148067.0003 and 148067.0012). Noting the variability in phenotype caused by mutations at the same codon or by identical mutations in different probands (see, e.g., 148067.0003), Smith et al. (2005) suggested that a combination of factors, genetic and environmental, might be involved in determining the overall clinical phenotype in keratin disorders.
In a Chinese mother and daughter with pachyonychia congenita, Du et al. (2012) identified heterozygosity for a KRT16 missense mutation (N125G; 148067.0013). The mother had severe hypertrophic dystrophy of the toenails in addition to palmoplantar keratoderma, whereas her 5-year-old daughter exhibited only focal plantar hyperkeratoses.
Lessard and Coulombe (2012) generated Krt16 -/- mice and observed failure to thrive and increased postnatal mortality, with more than 30% of mice dying within 24 hours of birth and over 60% before weaning age. The survivors continued to grow and gained weight but remained smaller and lighter than their littermate controls. Hyperplastic lesions on the dorsal midline posterior tongue were observed in all mutant mice by postnatal day 3 (P3). Surviving mice no longer had visible lesions, but tongue architecture showed thickened epithelium and loss of normal filiform papillae; the authors suggested that the oral lesions might be painful and affect feeding behavior. Starting at 4 to 6 weeks of age, Krt16 -/- mice developed prominent hyperkeratotic calluses of both the front and hind paws, particularly in areas of high physical impact, consistent with the KRT16-associated focal PPK observed in humans. Adult mutant mice were significantly less active than control animals, which the authors hypothesized was the result of substantial discomfort due to the palmoplantar lesions. Reduced filaggrin expression in established front paw calluses was observed, indicating focal loss of barrier protection. In contrast to human disease, nail morphology was not affected in Krt16 -/- mice.
In a sporadic case of the Jadassohn-Lewandowsky type of pachyonychia congenita (PC1; 167200), McLean et al. (1995) identified heterozygosity for a leu132-to-pro (L130P) mutation in the helix initiation motif of keratin-16. An alternative designation for this mutation is L15P.
In 2 probands with pachyonychia congenita, Smith et al. (2005) identified heterozygosity for a c.395T-C transition in the KRT16 gene, resulting in the L130P substitution.
In a 4-generation family with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), previously studied by Stevens et al. (1994), in which affected individuals also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an arg127-to-cys (R127C) substitution in the KRT16 gene at a highly conserved residue in the helix initiation motif of the 1A domain. The mutation was not found in unaffected family members or 20 controls. An alternative designation for this mutation is R10C.
In a sporadic patient with FNEPPK, Smith et al. (2005) identified heterozygosity for a c.379C-T transition in the KRT16 gene, resulting in the R127C substitution. The patient exhibited palmoplantar keratoderma without nail changes or oral lesions.
In a father and daughter with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), who also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an asn125-to-ser (N125S) substitution in the KRT16 gene at a highly conserved residue in the helix initiation motif of the 1A domain. The mutation was not found in 20 controls. An alternative designation for this mutation is N8S.
In 2 probands, 1 from a family with pachyonychia congenita (PC1; 167200) and 1 from a family with FNEPPK, Smith et al. (2005) identified heterozygosity for a c.374A-G transition in KRT16, resulting in the N125S substitution. The proband from the family with PC showed typical hypertrophic nail dystrophy in 17 of 20 nails, whereas the proband from the FNEPPK family exhibited no nail thickening and had only minor splinter hemorrhages of the nails.
In a sporadic case of pachyonychia congenita described as the Jadassohn-Lewandowsky type (PC1; 167200), Smith et al. (1999) identified heterozygosity for a 3-bp deletion (c.388del3) in the KRT16 gene, resulting in deletion of ser130. Using a genomic PCR system, they carried out the first prenatal diagnosis of this disorder using CVS material and correctly predicted a normal fetus.
In a family of Dutch origin with pachyonychia congenita described as the Jadassohn-Lewandowsky type (PC1; 167200), Smith et al. (1999) identified a heterozygous c.380G-C transversion in the KRT16 gene, resulting in an arg127-to-pro (R127P) amino acid change, using a novel long-range PCR strategy that eliminated amplification of KRT16 pseudogenes. This mutation affected the helix 1A domain of the KRT16 polypeptide.
In a family of Hungarian origin with pachyonychia congenita-1 (PC1; 167200), Smith et al. (1999) identified a heterozygous c.365A-C transversion in the KRT16 gene, resulting in a gln122-to-pro (Q122P) amino acid change, using a novel long-range PCR strategy that eliminated amplification of KRT16 pseudogenes. This mutation affected the helix 1A domain of the KRT16 polypeptide.
In a father and son with pachyonychia congenita-1 (PC1; 167200), Smith et al. (2000) identified heterozygosity for a c.371T-G transversion in the KRT16 gene, resulting in a leu124-to-arg (L124R) substitution in the 1A domain of the K16 polypeptide. The mutation was not found in 50 unrelated controls. Expression of mutant K16 in the PtK2 epithelial cell line produced complete collapse of the endogenous keratin cytoskeleton into dense aggregates.
In a girl with late-onset pachyonychia congenita (PC1; 167200), Connors et al. (2001) reported a lys354-to-asn (K354N) mutation in the central 2B domain of the KRT16 polypeptide. The amino acid substitution resulted from a c.1062A-T transversion in exon 6. The authors noted that this was the first time a mutation had been described in this location in a keratin other than KRT14. KRT14 mutations in region 2B (e.g., 148066.0005 and 148066.0012) result in milder phenotypes. It was unclear whether the position of the mutation was sufficient to explain the late-onset PC phenotype.
In a patient with sporadic pachyonychia congenita-1 (PC1; 167200), Terrinoni et al. (2001) reported a met121-to-thr (M121T) mutation in the KRT16 protein that arose from a c.362T-C transition. This mutation in the 1A domain is also referred to as M4T.
In a patient with sporadic pachyonychia congenita-1 (PC1; 167200), Terrinoni et al. (2001) reported a leu128-to-gln (L128Q) mutation in the KRT16 protein that arose from a c.383T-A transversion. This mutation in the 1A domain is also referred to as L11Q.
In a 3-generation family with mild focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), Smith et al. (2000) identified heterozygosity for a complex deletion in exon 6 of the KRT16 gene, involving a 23-bp deletion (c.1244del23) together with a 1-bp deletion downstream (c.1270delG), resulting in a deletion of 8 residues and a substitution of 2 residues in the conserved helix termination motif (HTM) of the K16 polypeptide. Expression of the deleted K16 in the PtK2 epithelial cell line produced aggregates larger than those seen with an L124R mutation (148067.0007), and some residual endogenous keratin was seen in filamentous form, implying that the deletion mutation may render the mutant K16 protein less able to integrate into and disrupt the endogenous network, thus resulting in a milder phenotype.
In a proband with severe hypertrophic nail dystrophy affecting both hands and feet (PC1; 167200), Smith et al. (2005) identified heterozygosity for a c.373A-G transition in the KRT16 gene, resulting in an asn125-to-asp (N125D) substitution in the highly conserved helix initiation motif of the 1A domain.
In a 36-year-old Chinese woman with pachyonychia congenita (PC1; 167200), Du et al. (2012) identified heterozygosity for a c.373_374AA-GG transition in the KRT16 gene, resulting in an asn125-to-gly (N125G) substitution within the 1A rod domain. The proband had severe hypertrophic nail dystrophy of her toenails and palmoplantar keratoderma, whereas her 5-year-old daughter, who also carried the mutation, showed only focal plantar hyperkeratosis at pressure points, without any nail or hand involvement. Both patients reported hyperhidrosis of the hands and feet. The mutation was not found in unaffected family members or in 100 controls.
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