Background
Palmoplantar keratoderma (PPK) is a heterogeneous entity of both genetics and acquired keratinization disorder, which is characterized by persistent marked epidermal thickening of palms and soles [
1]. Hereditary PPKs comprising an increasing number of entities with different prognoses, which may be associate with cutaneous and extracutaneous manifestations [
2].
Depending on different patterns of hyperkeratosis, PPKs are further classified into four distinct types: diffuse, striate, focal and punctate [
3,
4]. So far, deleterious mutations in > 20 genes have been reported in pathogenesis of different forms of hereditary PPKs [
3,
4]. In last few years, advent of cutting edge genetic techniques such as whole genome microarray scans and whole exome sequencing have incredibly accelerated the identification of disease causing variants in many genes involved in various inherited forms of PPKs, and thus significantly increasing understanding about intricate molecular mechanisms of heterogeneous disorders, consecutively aiding valuable genetic counselling and patient care [
3].
Mal de Meleda (MDM), a type of transgradient palmoplantar keratoderma (PPK), is a rare autosomal recessive disorder. Luca Stulli, a Croatian born scientist in 1826 first described Mal de Meleda on the Adriatic Meleda island (now Mljet) [
5]. The disease can feature other potentially disfiguring effects on the hands and feet that can severely impact function.
The disease onset is soon after birth and is clinically characterized by erythema, transgradients and progradients hyperkeratosis of palms and soles with well demarcated borders and hypohydrosis. Other associated features are brachydactyly, nail abnormalities and lichenoid plaques [
6]. Rigorous keratoderma can lead to deformity in hands and feet and gradually this may results into severe impairment [
7,
8].
Furthermore, previous reports have shown that MDM may be caused due to mutations in the
SLURP1 gene (previously known as ARS-B gene) encoding a secreted toxin-like mammalian lymphocyte antigen 6/urokinase-type plasminogen activator receptor-related protein 1(
SLURP1). Expression of
SLURP1 is reported in epithelium, stomach, sensory nerve cells, gums, esophagus and immune cells with highest level in keratinocytes especially in palms and soles [
9‐
11].
Striate PPK type I is a rare type of PPK and shows the autosomal dominant mode of inheritance associated with
DGS1 heterozygous mutation. Clinical features of this condition are linear hyperkeratotic lesions on the palms extending along the length of fingers and associated with thick patches of diffuse hyperkeratosis on the soles [
12].
Heterozygous mutation in
DSG1 gene in an autosomal dominant pattern have also been reported in focal PPK in a Libyan family, and in a Jewish Yemenite family with diffuse PPK [
13,
14], a discovery which elucidates that different patterns of palmoplantar involvement may result from mutations in the
DSG1 gene. Additionally, bi-allelic mutations in
DSG1 gene have also been recently reported in the severe SAM syndrome, characterized by sinusitis, palmoplantar keratoderma, erythroderma, multiple allergies and metabolic defects, with heterozygous mutation carriers only presenting hyperkeratotic palmoplantar lesions [
15].
Here we report findings regarding investigations of two families from Pakistan with clinically-defined PPK, for which the specific genetic basis was unclear.
Discussion
SLURP1 has been localized to the granular layer of epidermis [
16], where it functions as part of nicotinic acetylcholine receptors found on keratinocyte cells as a pro-apoptotic protein [
17]. Arredondo et al. [
17] demonstrated that keratinocytes are stimulated by SLURP1 through nicotinic acetylcholine receptor, leading to decline in keratinocytes cell number, indicative of the inhibitory and regulatory nature of SLURP1. Therefore, when SLURP1 is non-functional, as seen in Mal de Meleda, severe hyperkeratosis results due to improper keratinocyte apoptosis regulation [
8,
18].
We identified nonsense variant in family 1 which causes substitution of evolutionarily conserved tryptophan at 15th amino acid position in
SLURP1 by a premature termination codon. Nonsense variant (c.129C > A; p.Cys43*) is also reported in exon 2 of
SLURP1 gene in a Turkish family. Similarly another nonsense mutation (c.286C > T; p.Arg96*) is also found in exon 3 in Croatian family and is predicted to truncate protein synthesis via nonsense-mediated mRNA decay [
19,
20]. Family reported in this study have same clinical features to previously reported Mal de Meleda families.
The
SLURP1 gene mutation p.Gly86Arg is most often found in sporadic patients with MDM of Asian origin [
21,
22].
So far 20 mutations in
SLURP1 are reported to cause Mal de Meleda, a form of PPK (Additional file
1: Table S1,). c.44G > A; p.Trp15Term is the second variant identified in Pakistan apart from c.2 T > C, p.Met1Thr variant which was recently reported [
23].
“Desmoglein” comprises of the two Greek words “desmos” for “tie” and “glein” for “glue-like.” Perturbations of desmoglein expression in the epidermis have been known to impact cell adhesion properties.
DSG1 is distinctively located, just above the stratum germinativum, to be candidate of epidermis stratification and differentiation [
24]. A study in which
DSG1 was down regulated in skin culture confirmed the importance of
DSG1 for directing those functions [
25].
In all reported PPKs cases where
DSG1 gene variants (frameshift or nonsense) have been reported, there is evidence that affected protein haploinsufficiency leads to the striate, focal PPK and striate PPK with wooly hair and cardiomyopathy. Haploinsufficiency is predicted to cause through nonsense mediated mRNA decay because of premature termination codons [
26,
27]
. Interestingly, a heterozygous
DSG1 mutation has also been reported in focal PPK [
13].
To date, 31 mutations (8 nonsense mutations, 14 frame-shift variants and 9 splice-site variants) in
DSG1 have been reported to cause striate/focal PPK (Additional file
1: Table S2). In 2009, Dua-Awereh et al. reported five heterozygous variants (p.Arg26*; c.373-2A > G; c.515C > T; c.1266-3C > G and c.1399delA) in
DSG1 gene in five families with autosomal dominant striate PPK [
28]. Thus, c.133C > T; p.Arg45* variant identified in this study is the sixth mutation underlying dominantly inherited form of striate PPK in Pakistan.
MDM presented a consistently severe phenotype than Nagashima form of PPK. MDM shows progressive hyperkeratosis among all PPKs and causes flexion contracture and constricting band [
29]. While, Nagashima PPK is characterized by non-progressive and mild hyperkeratosis and does not show flexion contracture and constricting band [
30,
31]
. Nagashima PPK is caused by biallelic loss of function mutation in
SERPINB7 while, MDM is caused by
SLURP1 gene mutation [
20]. Therefore, MDM is genetically distinct from Nagashima PPK [
32]
. PPKs are diagnosed on the basis of differential diagnosis to find out the disease entity. Differential diagnosis of PPK is summarized in Table
2.
Table 2
Differential diagnosis of PPKs
Mal de Meleda |
Diffuse PPK
| 1. Soon after birth 2.Severe diffuse yellow and waxy thick hyperkeratosis in a ‘glove-and-socks’ distribution 3.Sharp demarcation 4. Autosomal Recessive | 1.Nonepidermolytic pattern 2.Increased stratum lucidum 3.Prominent perivascular inflammatory infiltrate |
SLURP1
|
Unna-Thost | 1.Soon after birth to early childhood 2.Diffuse yellowish thick hyperkeratosis with sharp demarcation at the volar border 3. Autosomal Dominant | 1.Epidermolytic pattern (perinuclear vacuolization and granular degeneration of keratinocytes in the spinous and granular layer) |
KRT1, KRT9
|
Greither Disease | 1.Soon after birth to childhood/adolescence 2. Diffuse red/yellow moderate to severe hyperkeratosis 3. Autosomal Dominant | 1.Epidermolytic pattern |
KRT1
|
Nagashima PPK | 1.Mostly within infancy 2. Diffuse mild reddish hyperkeratosis, red rim; white spongy appearance after water exposure 3. Autosomal Dominant | 1.Nonepidermolytic pattern |
SERPINB7
|
Striate PPK |
Striate Type I PPK |
Focal PPK
| 1.Childhood to adolescence 2. Linear hyperkeratotic distribution on palms and palmar surface of the fingers 2.Focal hyperkeratosis at trauma-prone sites on soles 3.Autosomal Dominant | 1.Hyperkeratosis 2. Widening of intercellular spaces in the spinous and granular layer |
DSG1
|
Striate Type II PPK | 1.Childhood to early adulthood 2. Linear hyperkeratotic distribution on palms and palmar aspect of fingers 3.Focal hyperkeratosis at trauma-prone sites on soles 4. Autosomal Dominant | 1.Hyperkeratosis 2.Widening of intercellular paces and condensation of the keratin filament network in suprabasal cell layers |
DSP
|
Punctate PPK |
Punctate PPK Type IA |
Focal PPK
| 1.Late childhood to adulthood 2.Multiple hyperkeratotic papules with central indentation 3.Worsening of papules upon exposure to water 4. Autosomal Dominant | 1.Hyperkeratosis and hypergranulosis with central epidermal depression |
AAGAB
|
Punctate PPK Type IB | 1.Late childhood to adulthood 2.Multiple hyperkeratotic papules with central indentation 3. Autosomal Dominant | 1.Hyperkeratosis and hypergranulosis with central epidermal depression |
COL14A1
|
Punctate PPK Type II | 1.Puberty to early adulthood 2.Multiple spiny keratosispits with keratotic plugs (late onset) 4. Autosomal Dominant | 1. Columns of parakeratotic corneocytes (cornoid lamellae) 2.Superficial epidermal depression where the granular layer is reduced or absent | Unknown |
Punctate PPK Type III | 1.Adolescence to adulthood 2.Translucent hyperkeratotic papules, sometimes umbilicated, on lateral aspects of palms and soles 3. Autosomal Dominant | 1.Hyperkeratosis and hypergranulosis 2.Decreased number of fragmented elastic fibres | Unknown |
Conclusion
The identification of a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of PPK in the Pakistani families investigated alongside a review of previously reported variants adds to knowledge of the molecular causes of these conditions. Additionally, the data here provides important information regarding the nature, spectrum and molecular basis of PPK in Pakistan, enabling early clinical intervention, increased awareness regarding inherited disorders present in a community, and aiding diagnosis and counselling.
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