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Yuval Ramot1, Abraham Zlotogorski1, Maurice van Steensel2,3,4
1 Department of Dermatology, Hadassah - Hebrew University Medical
Center, Jerusalem, Israel
2 School of Medicine and School of Life Sciences, University of
Dundee, United Kingdom
3 Institute of Medical Biology, Singapore
4 Lee Kong Chian School of Medicine, Nanyang Technological
In their rec...
In their recently published article, Shah et al. claim that a
homozygous loss-of-function mutation in KRT83 leads to recessive
progressive symmetric erythrokeratoderma.1 However, since KRT83 encodes a
hair-specific keratin, we believe it is highly unlikely that a mutation in
this gene would cause a strictly epidermal phenotype.
Keratins are intermediate filaments that provide structural support
to epithelial cells, in addition to other biological properties.2-4 They
are unique in that each has a very specific expression pattern, which has
been studied extensively.5 To date, mutations in hair keratins have all
been associated with phenotypes restricted to the hairs and nails.6
Specifically, mutations in KRT83 had been linked exclusively to
Progressive symmetric erythrokeratoderma and erythrokeratoderma
variabilis do not present with a hair phenotype. These strictly epidermal
disorders are presently grouped together as erythrokeratodermia variabilis
et progressiva (OMIM #133200) because they have the same molecular basis -
mostly autosomal dominant mutations in GJB3 and GJB4.9 The encoded
proteins are highly expressed in the epidermis.9,10
In their discussion, the authors state that keratin K83 is also
expressed outside of the hair follicle. They claim that Kb23, which is the
rat ortholog for K83, is expressed in the whole skin, but the reference
that they cite has only demonstrated expression in the hair follicle, and
not the epidermis.11 The same is true for the claimed expression in the
sheep wool follicles, where the reference cited shows expression only in
the wool follicle, and not the epidermis.12 Shah et al. also claim that
according to the human protein atlas, K83 is expressed in the skin, but
actually, it was found only in the hair and not in the epidermis
(http://www.proteinatlas.org/ENSG00000170523-KRT83/tissue). Staining as
shown in the atlas is highly restricted, even though the antibody used in
the human protein atlas is likely to recognize additional hair keratins.
The expression atlas that is also cited in the article gives information
on expression patterns of genes (http://www.ebi.ac.uk/gxa/home), and is
not based on immunohistochemistry as stated by the authors. Since the skin
samples used for expression profiling in this database are of whole skin
and not the epidermis alone, they are likely to also include parts of hair
follicles. Obviously, expression of KRT83 could be observed in these
samples. In contrast, a large number of studies demonstrate robust,
specific and reproducible expression of K83 in the hair.5,13-15 Thus, we
feel that it is safe to conclude that K83 is hair-specific and is not
expressed in human epidermis.
We consider it unlikely that mutations in a keratin that is
exclusively expressed in the hair would cause a severe epidermal phenotype
that also involves the palms and soles, areas that are devoid of hair
follicles. If they did, there would be profound implications for our
understanding of keratins, and of skin biology in general. We believe that
such a provocative claim should have been accompanied by proper
demonstration that K83 is indeed expressed in the epidermis, and
functional evidence that its loss can lead to an epidermal-specific
1 Shah K, Ansar M, Mughal ZU et al. Recessive progressive symmetric
erythrokeratoderma results from a homozygous loss-of-function mutation of
KRT83 and is allelic with dominant monilethrix. J Med Genet 2016, Dec 13,
Epub ahead of print.
2 Ramot Y, Zlotogorski A. Keratins: the hair shaft's backbone
revealed. Exp Dermatol 2015; 24: 416-7.
3 Ramot Y, Paus R. Harnessing neuroendocrine controls of keratin
expression: a new therapeutic strategy for skin diseases? Bioessays 2014;
4 Ramot Y, Paus R, Tiede S et al. Endocrine controls of keratin
expression. Bioessays 2009; 31: 389-99.
5 Moll R, Divo M, Langbein L. The human keratins: biology and
pathology. Histochem Cell Biol 2008; 129: 705-33.
6 Ramot Y, Zlotogorski A. Molecular genetics of alopecias. Curr Probl
Dermatol 2015; 47: 87-96.
7 van Steensel M, Vreeburg M, Urbina MT et al. Novel KRT83 and KRT86
mutations associated with monilethrix. Exp Dermatol 2015; 24: 222-4.
8 van Steensel MA, Steijlen PM, Bladergroen RS et al. A missense
mutation in the type II hair keratin hHb3 is associated with monilethrix.
J Med Genet 2005; 42: e19.
9 van Steensel MA, Oranje AP, van der Schroeff JG et al. The missense
mutation G12D in connexin30.3 can cause both erythrokeratodermia
variabilis of Mendes da Costa and progressive symmetric
erythrokeratodermia of Gottron. Am J Med Genet A 2009; 149A: 657-61.
10 Ishida-Yamamoto A, McGrath JA, Lam H et al. The molecular
pathology of progressive symmetric erythrokeratoderma: a frameshift
mutation in the loricrin gene and perturbations in the cornified cell
envelope. Am J Hum Genet 1997; 61: 581-9.
11 Nanashima N, Akita M, Yamada T et al. The hairless phenotype of
the Hirosaki hairless rat is due to the deletion of an 80-kb genomic DNA
containing five basic keratin genes. J Biol Chem 2008; 283: 16868-75.
12 Yu Z, Wildermoth JE, Wallace OA et al. Annotation of sheep keratin
intermediate filament genes and their patterns of expression. Exp Dermatol
2011; 20: 582-8.
13 Langbein L, Yoshida H, Praetzel-Wunder S et al. The keratins of
the human beard hair medulla: the riddle in the middle. J Invest Dermatol
2010; 130: 55-73.
14 Langbein L, Schweizer J. Keratins of the human hair follicle. Int
Rev Cytol 2005; 243: 1-78.
15 Langbein L, Rogers MA, Winter H et al. The catalog of human hair
keratins. II. Expression of the six type II members in the hair follicle
and the combined catalog of human type I and II keratins. J Biol Chem
2001; 276: 35123-32.