IS c.1431-12G>A A COMMON EUROPEAN MUTATION
OF SPINK5? REPORT OF A PATIENT WITH
NETHERTON SYNDROME
Śmigiel R, Królak-Olejnik B, Śniegórska D, Rozensztrauch A,
Szafrańska A, Sasiadek MM, Wertheim-Tysarowska K
*Corresponding Author: Robert Śmigiel, M.D., Ph.D., Department of Pediatrics, Wroclaw Medical University, Bartla 5,
PL 51-618 Wroclaw, Poland. Tel: +48-71-784-13-26. Fax: +48-71-784-00-63. E-mail: robert.smigiel@ umed.wroc.pl
page: 81
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DISCUSSION
LEKTI1 is expressed in epithelial, thymus, tonsils,
parathyroid glands, hair follicles and the trachea [3], but the
vast majority of data concerning its biology and functions
comes from epithelium research. The spectrum of LEKTI1
activity as a serine protease inhibitor is wide and it has been
shown that LEKTI1 is not only expressed as full-length
protein (145 kDa), but also as two other isoforms (a short
one: 125 kDa, and a long one: 148 kDa). Furthermore, full
length isoform in addition to its own activity, undergoes
several proteolytic cleavages, resulting in generation of
various LEKTI1 domains with different inhibitory specificities
[2]. Various LEKTI1 derived poly-peptides inhibit
KLK5, KLK7 and KLK14 (kallikrein-related peptidases)
and it is hypothesized that deficient inhibition of those
proteins is one of the major causes of epidermal symptoms
observed in NS [1,4]. Hovnanian [2] proposed that as a result
of LEKTI1 deficiency, KLK5, KLK7 and ELA2 (elastase
2) are improperly activated leading to abnormal skin
desquamation, development of proinflammatory response
together with abnormalities of lipids and improper profilaggrin
processing. This mechanism triggers further actions,
which, together with higher penetration of microbes and
allergens, aggravate proin-flammatory response leading to
development of NS symptoms [2,6,7].
According to Human Gene Mutation Database
(HGMD) data, 72 distinct mutations were reported to cause
NS, of which only two are missenses and others result in
premature termination codon (PTC), frameshifts or splicing
disruptions [8]. Similarly, the mutations identified in our
patient are predicted to affect splicing. According to bioinformatics
analyzes, the c.1431-12G>A introduces novel
acceptor splicing site 10 nucleotides upstream of exon 16,
while unreported before c.1816_1820+21delinsCT abolishes
donor splicing site in intron 19, but also leads to a
frameshift. The c.1431-12G>A mutation was reported by
Raghunath et al. [9], who found it in two independent patients
originating from Bosnia (homozygote) and Austria
(heterozygote). Both parents of the Bosnian child were carriers
of this mutation and were reported not to be consanguineous.
Raghunath et al. [9] did not detect the LEKTI1
protein by immunohistochemical staining of skin biopsies
and/or immunoblot analysis of plucked hair roots from these
patients. These results and our data indicate that the majority
of SPINK5 mRNA is truncated in our patient. Importantly,
they do not rule out the possibility that small amount of full
length mRNA may also be produced. According to Lacroix
et al. [10], some deep intronic mutations activating cryptic
splicing sites, may not completely abolish the natural
splicing sites, allowing low level production of full length
protein. This phenomena was observed in the case of mutations
c.1820+ 53G>A and c.283-12T>A, and recognized to
possibly be linked with a milder phenotype. This was also
supported by analysis of residual expression of LEKTI1 in
cultures of NS patients’ (genotyped as c.1820+53G>A/p.
Cys297 Cys and c.283-12T>A/p.Cys297Cys) keratinocytes,
which proved that LEKTI1 fragments could be detected.
The p.Cys297Cys is an exonic silent variant that causes
disruption of exonic splicing enhancers and also introduces
a cryptic splicing site. Although Lacroix et al. [10] hypothesized
that p.Cys297Cys is fully penetrant, Fortugno et al.
[11] showed that p.Cys297Cys also does not cause complete
abolishing of natural splice sites and partial expression of
LEKTI1 is preserved [11].
Moreover, Bitoun et al. [12] suggest that certain PTCs
in SPINK5 do not lead to mRNA degradation and may be
used for truncated protein production. Primary structure of
full length LEKTI1 consists of 15 different serine proteases
inhibitory domains (D1-D15). As stated before, several
isoforms of LEKTI1 with distinct inhibitory activities are
expressed and/or subsequently generated. Thus, if truncated
proteins (due to PTC) are produced, some domains would
potentially be generated and functional. Komatsu et al. [13],
despite unsuccessful attempts to identify truncated proteins in
patients’ tissues, performed a series of experiments aimed at
differentiation of the profile of inhibitory activity of LEKTI1
in five NS patients. They showed that there is an adverse correlation
between the number of retained LEKTI1 domains
and clinical severity of NS. The more domains preserved,
the less severe clinical features such as skin lesions, growth
retardation, skin infections were noticed. Results of some
biochemical tests also supported these findings. With regard
to this theory, our patient may hypothetically have 1-7 and
1-9 domains retained. Although it is impossible to speculate
about the potential effect of their preservation, the Komatsu et
al. [13] results of an in vitro assay with recombinant polypeptides
containing different LEKTI1 domains, suggest that D6-
D9 seem to be responsible for dose-dependent inhibition of
trypsin, such as Phe-Ser-Arg, and chymotrypsin-like activity.
Despite a growing number of findings explaining the
molecular basis of phenotypic differences in NS patients,
we still do not understand them. The LEKTI1 is involved
in interaction with several proteins that play an important
role in epidermal biology. Although the NS phenotype
seems to be at least partially dependent on modifier genes
and environmental factors [2], the hypothesis concerning
preserved activity of LEKTI1 cannot be neglected. Correlation
studies need to be performed on a larger cohort
of patients that is always difficult in the case of orphan
diseases. Thus, we are convinced that the case presented
by us will provide further data for future studies. Furthermore,
our patient is the third proband reported to carry the
c.1431-12G>A mutation, thus our results provide evidence
that c.1431-12G>A can be referred to as a frequent central-
south European mutation of SPINK5. The majority of
mutations in this gene is family-specific, however, several
recurrent mutations have also been identified in different
populations. With only a few exceptions, these mutations,
similar to c.1431-12G>A, were mostly identified in two,
three or four unrelated families [10,12,14,15].
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