15 March 2005
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LETTER TO THE EDITOR
Homozygous Dominant Missense Mutation in Keratin 17
Leads to Alopecia in Addition to Severe Pachyonychia
Congenita
Journal of Investigative Dermatology advance online publication, 16 February 2012; doi:10.1038/jid.2011.484
TO THE EDITOR
Homozygosity for dominant mutations
in keratin genes is rare and has
only been reported for epidermolysis
bullosa simplex (EBS; Stephens et al.,
1995; Hu et al., 1997; Oldak et al.,
2011). The majority of pathogenic
variants reported in 23 keratin genes
are heterozygous missense or small
in-frame insertion/deletion mutations
inherited in an autosomal dominant manner (http://www.interfil.org;
Szeverenyi et al., 2008). A small
number of recessive cases have been
reported, mostly due to nonsense mutations (Yiasemides et al., 2008). Here,
we report homozygosity for dominant
missense mutations in keratin 17 that
modify the pachyonychia congenita
(PC) phenotype. PC is an autosomal
dominant skin disorder caused by
heterozygous mutations in any one of
the genes encoding keratins K6a, K6b,
K16, or K17 (McLean et al., 2011). The
main characteristics are palmoplantar
keratoderma, plantar pain, and nail
dystrophy. Additionally, oral leukokeratosis, follicular keratoses, and epidermal
cysts often occur. PC due to mutations in
K17 (termed PC-17) is more frequently
associated with neonatal teeth and widespread pilosebaceous cysts in adults.
Family 1, of Hispanic ancestry,
showed autosomal dominant inheritance (Figure 1a). A consanguineous
marriage between affected individuals
resulted in three affected (one homozygous (proband) and two heterozygous) and one unaffected offspring.
Both parents had some characteristics
of PC. The father had thickened nails,
mild plantar hyperkeratosis and steatocysts; the mother had steatocysts but
reported neither nail changes nor
keratoderma. The 10-year-old proband
had features typical of PC but was
much more severely affected than other
family members and had additional
features (Figure 1b–g). Unusually, all
nails were thickened at birth. He also
had several neonatal teeth. At 4 months
he developed leukokeratosis, and by
7 months had blistering on his hands
and feet, and thickening of palmoplantar skin that is now localized to
pressure points (Figure 1b, c, e, and f).
He continues to have painful blisters
and has follicular keratosis (Figure 1g).
He has no steatocysts to date, although
these generally develop at puberty. The
most unusual feature, not previously
associated with PC, was hair loss, first
noted at 7 months and has continued
during his lifetime (Figure 1d). On
examination he had a circumscribed
area in the occipital region where the
hairs were much shorter and thinner.
Eyebrows were normal. His affected
brother (25 years old) and sister
(13 years old) had thickened toenails,
slight thickening of fingernails with
splinter hemorrhages and widespread
steatocysts. Neither sibling had keratoderma, blistering, neonatal teeth nor
alopecia (Figure 1h–j). The brother’s
1-year-old daughter had nail involvement and a neonatal tooth.
Genomic DNA was obtained with
informed consent and appropriate
ethical approval that complies with
the Declaration of Helsinki Principles
(Western IRB study no. 20040468).
DNA extraction and mutation detection
were performed according to the published protocols that avoid pseudogene
contamination (Wilson et al., 2011).
Abbreviations: EBS, epidermolysis bullosa simplex; PC, pachyonychia congenita
& 2012 The Society for Investigative Dermatology
Two primer sets were used for each
mutation hotspot exon to ensure against
polymorphism. By DNA sequencing of
KRT17, a homozygous dominant missense mutation was identified, designated p.Asn92Ser (protein), c.275A4G
(DNA), in the proband of Family 1. The
mildly affected parents and siblings
were heterozygous (Figure 1k–n). Mutation p.Asn92Ser is the most commonly
reported mutation in KRT17, occurring
in 36% of PC-17 families (Wilson et al.,
2011).
Family 2 was of Middle Eastern
ancestry. The proband, a 32-year-old
male, had thickened finger and toenails
by 2 years of age (Figure 2a and b).
Painful blisters, calluses, fissures, and
ulcerations were present on hands and
feet (Figure 2c and e), and he had
follicular hyperkeratosis (Figure 2f
and g) but no oral leukokeratosis. He
developed generalized alopecia at the
age of 3 years and now has almost
total alopecia (Figure 2d, at age 8).
At the age of 7, the patient received
oral etretinate (Tigason; 1 mg kg 1 per
day) for 3 months, which reduced
the follicular hyperkeratosis but did
not improve the plantar blisters, alopecia, or pachyonychia. His parents were
reportedly unrelated but unfortunately
were not available for examination or
DNA sampling. The father was reported
to have steatocysts. The proband of
Family 2 was homozygous for dominant missense mutation p.Arg94Cys,
c.280C4T in KRT17 (Figure 2h and i).
The proband was homozygous for
microsatellite markers spanning type I
keratin locus. Mutation p.Arg94Cys has
been reported in several cases of dominant PC-17 (http://www.interfil.org).
To our knowledge, homozygous
dominant missense mutations have not
www.jidonline.org
1
NJ Wilson et al.
Homozygous Missense Mutation in Keratin 17
?
I
?
II
III
5
4
IV
V
Normal K17, exon 1
2
Journal of Investigative Dermatology
K17 p.Asn92Ser
K17 p.Asn92Ser
Homozygous (proband) Heterozygous (mother)
K17 p.Asn92Ser
Heterozygous (father)
NJ Wilson et al.
Homozygous Missense Mutation in Keratin 17
Normal K17, exon 1
K17 p.Arg94Cys
Homozygous (proband)
Figure 2. Clinical features and mutational analysis of KRT17 in Family 2. Clinical pictures of proband of Family 2, at age 8, showing (a) thickened toenails and
(b) finger nails; (c) painful blisters on the feet; (d) generalized alopecia; (e) plantar keratoderma and blisters; (f) follicular hyperkeratosis on the knees; and
(g) follicular hyperkeratosis on the elbow. Molecular genetic analysis of KRT17. (h) Normal KRT17 sequence in exon 1, showing nucleotides 271–285. (i) The
equivalent region as in (h) from the proband showing homozygous transition mutation c.280C4T (arrow) leading to amino-acid substitution p.Arg94Cys.
Figure 1. Pedigree, clinical features, and mutational analysis of KRT17 in Family 1. (a) Pedigree of Family 1. Clinical pictures of proband (IV-5) of Family 1
showing: (b) blistering and keratoderma on the soles of the feet; (c) thickened toenails; (d) region of the scalp showing loss of hair; (e) thickening of all 10
fingernails; (f) extremely thickened fingernail; and (g) follicular keratosis. Clinical pictures IV-4, sister of proband of Family 1 showing: (h) slight thickening of the
fingernails with some splinter hemorrhages; (i) steatocysts on the forehead; and (j) thickened toenails. Molecular genetic analysis of KRT17. (k) Normal KRT17
sequence in exon 1 showing nucleotides 271–285. (l) The equivalent region as in (k) from the proband showing homozygous missense transition c.275A4G
(arrow) leading to amino-acid substitution p.Asn92Ser. (m) The equivalent region as in (k) from the mother showing heterozygous mutation c.275A4G (arrow)
leading to amino-acid substitution p.Asn92Ser. (n) The equivalent region as in (k) from the father showing heterozygous mutation c.275A4G (arrow) leading to
amino-acid substitution p.Asn92Ser.
www.jidonline.org
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NJ Wilson et al.
Homozygous Missense Mutation in Keratin 17
been previously reported in PC. However, both these mutations are commonly seen as heterozygous mutations,
with p.Asn92Ser being the most commonly reported mutation in KRT17.
Interestingly, both mutations, p.Asn92Ser and p.Arg94Cys, have been reported to show phenotypic variation: most
commonly giving rise to PC-17 (http://
www.interfil.org) but occasionally steatocystoma multiplex (Covello et al.,
1998; Wang et al., 2009). Intra-familial
phenotypic variation, as seen here
between affected heterozygous members of Family 1, has previously been
reported (Smith et al., 1997).
Of the three reported cases of
homozygosity for a dominant mutation
in another keratin disorder, EBS, two
mutations were described as partially
dominant (or semidominant)—homozygous individuals were more severely
affected than heterozygotes (Hu et al.,
1997; Oldak et al., 2011). However, in
a third EBS family, homozygosity for a
mutation in KRT5 did not alter clinical
severity (Stephens et al., 1995).
In the families studied here, the
features typical of PC were more severe
in the homozygous cases than heterozygotes, again indicating a gene dosage
effect. The additional feature of hair
loss, seen in both cases, is particularly
interesting as alopecia has not been
previously reported in the cases of
mutation-confirmed PC. K17 is expressed
in the hair follicle (Moll et al., 2008),
and we hypothesize that the increased
dosage of mutant K17 in the homozygotes crosses a threshold where hair
abnormalities become evident. K17-null
mice develop hair fragility during the
first week after birth resulting in severe
4
Journal of Investigative Dermatology
alopecia (McGowan et al., 2002), showing that this protein is critically important
for hair follicle function.
Individuals homozygous or compound heterozygous for dominant mutations have a much greater risk of having
affected offspring (essentially 100%),
compared with heterozygous carriers of
a dominant mutation (50%). Therefore,
in terms of genetic testing, homozygous
or compound heterozygous mutations
should be especially sought in PC
patients who present with alopecia. As
four keratin genes are involved in
dominant PC, bigenic inheritance is also
a possibility in unusually severe cases
resembling those reported here.
CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS
We thank the patients for participating in this
study. FJDS and NJW are supported by the
Pachyonychia Congenita Project (http://www.
pachyonychia.org).
Neil J. Wilson1, Mónica L. Cárdenas
Pérez2, Anders Vahlquist3,
Mary E. Schwartz4, C. David Hansen5,
W.H. Irwin McLean1 and
Frances J.D. Smith1
1
Dermatology and Genetic Medicine, Division
of Molecular Medicine, University of Dundee,
Dundee, UK; 2Department of Dermatology,
University of Valle, Cali, Colombia;
3
Department of Medical Sciences,
Uppsala University, Uppsala, Sweden;
4
PC Project, Salt Lake City, Utah, USA and
5
Department of Dermatology, University of
Utah, Salt Lake City, Utah, USA
E-mail: [email protected]
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