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of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate
dehydrogenase deficiency. J Lipid Res.59(12):2413-2420.
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Autosomal recessive congenital ichthyoses in the Czech Republic. Br. J .Dermatol. 174 (2)
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[21] J. Fischer. Autosomal recessive congenital ichthyosis. J. Invest. Dermatol. 129 (6)
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[22] C.M. Henry, G.P. Sullivan, D.M. Clancy, I.S. Afonina, D. Kulms, S.J. Martin. NeutrophilDerived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines. Cell
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fingerprinting shows profound TH17 skewing and a unique barrier genomic signature. J. Allergy
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[24] A.S. Paller. Profiling immune expression to consider repurposing therapeutics for the
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Ichthyoses. J. Invest. Dermatol. 139 (3) (2019):535-540.
[25] A.S. Paller, Y. Renert-Yuval, M. Suprun, H. Esaki, M. Oliva, T.N. Huynh, et al. An IL-17-
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dominant immune profile is shared across the major orphan forms of ichthyosis. J. Allergy Clin.
Immunol. 139 (1) (2017):152-165.
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Figure Legends
Figure 1. The ichthyotic skin lesions of the patient.
He had generalized, moderate hyperkeratosis with white to gray scales (A, B, back; C,
chest and abdomen; D, abdomen).
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Figure 2. Clinical features of the patient before, one month and two months after
the oral retinoid treatment.
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A-C, Hyperkeratotic and scaly lesions in the forearm, the upper arm, the palm and the
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sole of the patient before (A), one month (B) and two months (C) after the oral
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etretinate treatment. The patient’s skin symptoms were gradually improved for 2
months with the oral etretinate treatment.
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Figure 3. Histopathological and immunohistochemical findings and the NIPAL4
mutation causative of ARCI in the present patient.
A, B, Light microscopy shows compact hyperkeratosis in the patient’s epidermis in the
upper arm and the sole. (hematoxylin-eosin (HE)) None of the characteristic
histopathological features of psoriasis or pityriasis rubra pilaris, including inflammatory
cell infiltration in the superficial dermis, Munro’s microabscesses, parakeratosis, and
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Page 25 of 49
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Murase et al.
hypogranulosis and follicular keratin plugs, are observed in the upper arm or the sole.
C, Sanger sequencing of the patient’s genomic DNA revealed a homozygous mutation
c.1202delT in NIPAL4 in the patient. His mother was heterozygous for the identical
mutation.
D, The epidermis of the patient’s skin was positively stained with the anti-NIPAL4
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antibody (original magnification x100). There was no significant difference in NIPAL4
staining patterns and strength between the patient’s skin and a healthy control skin.
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E, The patient’s epidermis was strongly positive for anti-IL-36γ staining, compared with
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the faint staining in the epidermis of a healthy control skin sample (original
magnification, x 100).
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Figure 4. Analysis of the SC lipid using tape stripped stratum corneum samples
from the patient and 13 healthy individuals
A) In the upper arm of the patient, the total amount of ceramide was reduced compared
with those in the healthy controls. After treatment for two months (2M), in the upper
arm of the patient, the reduction of total amount of ceramides was not seen, whereas
there was no significant change in the forearm. B) The amount of CER[NS] was
increased both in the forearm and in the upper arm of the patient, whereas those of
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Journal of Dermatological Science
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Murase et al.
CER[AH], CER[AP], CER[EOH] and CER[EOP] were reduced in both lesions. After
the treatment, in both lesions, the amounts of CER[EOH] and CER[EOP] were
increased. An asterisk (*) under the ceramide classes indicates that there were ±２SD
difference between normal control and the patient before the treatment (0M). C) The
compositions of the CER[NS] with C32-35 were reduced, while those of the CER[NS]
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with C 46-54 were not. Asterisks (*) under the carbon chain lengths indicate that there
were more than ±2SD difference between normal controls and the patient before the
iew
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treatment (0M).
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Figure 5. Analysis of acylceramides in the SC using tape stripped samples.
Before the treatment (0M), CER[EOS], CER[EOH], and CER[EOP] with some carbon
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Page 26 of 49
chain-lengths were significantly reduced in the upper arm of the patient. Asterisks (*)
under the ceramide classes indicate that there were more than ±2SD difference between
normal control and the patient’s specimens before the treatment (0M). After the oral
etretinate treatment for two months (2M), CER[EOS] with C66:2-70:2 was reduced in
the forearm, and was slightly reduced or almost stable in the upper arm, compared with
that before the treatment (0M). On the other hand, most CER[EOH] and CER[EOP]
with C66:2-70:2 was increased after the treatment (2M).
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Fo
Figure 1. The ichthyotic skin lesions of the patient. He had generalized, moderate hyperkeratosis with
white to gray scales (A, B, back; C, chest and abdomen; D, abdomen).
254x190mm (96 x 96 DPI)
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Figure 2. Clinical features of the patient before, one month and two months after the oral retinoid
treatment. A-C, Hyperkeratotic and scaly lesions in the forearm, the upper arm, the palm and the sole of
the patient before (A), one month (B) and two months (C) after the oral etretinate treatment. The patient’s
skin symptoms were gradually improved for 2 months with the oral etretinate treatment.
338x451mm (96 x 96 DPI)
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Journal of Dermatological Science
iew
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Fo
Figure 3. Histopathological and immunohistochemical findings and the NIPAL4 mutation
causative of ARCI in the present patient. A, B, Light microscopy shows compact hyperkeratosis in the
patient’s epidermis in the upper arm and the sole. (hematoxylin-eosin (HE)) None of the characteristic
histopathological features of psoriasis or pityriasis rubra pilaris, including inflammatory cell infiltration in the
superficial dermis, Munro’s microabscesses, parakeratosis, and hypogranulosis and follicular keratin plugs,
are observed in the upper arm or the sole. C, Sanger sequencing of the patient’s genomic DNA revealed a
homozygous mutation c.1202delT in NIPAL4 in the patient. His mother was heterozygous for the identical
mutation. D, The epidermis of the patient’s skin was positively stained with the anti-NIPAL4 antibody
(original magnification x100). There was no significant difference in NIPAL4 staining patterns and strength
between the patient’s skin and a healthy control skin. E, The patient’s epidermis was strongly positive for
anti-IL-36γ staining, compared with the faint staining in the epidermis of a healthy control skin sample
(original magnification, x 100).
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602x451mm (96 x 96 DPI)
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Fo
Figure 4. Analysis of the SC lipid using tape stripped stratum corneum samples from the patient
and 13 healthy individuals. A) In the upper arm of the patient, the total amount of ceramide was reduced
compared with those in the healthy controls. After treatment for two months (2M), in the upper arm of the
patient, the reduction of total amount of ceramides was not seen, whereas there was no significant change
in the forearm. B) The amount of CER[NS] was increased both in the forearm and in the upper arm of the
patient, whereas those of CER[AH], CER[AP], CER[EOH] and CER[EOP] were reduced in both lesions. After
the treatment, in both lesions, the amounts of CER[EOH] and CER[EOP] were increased. An asterisk (*)
under the ceramide classes indicates that there were ±２SD difference between normal control and the
patient before the treatment (0M). C) The compositions of the CER[NS] with C32-35 were reduced, while
those of the CER[NS] with C 46-54 were not. Asterisks (*) under the carbon chain lengths indicate that
there were more than ±2SD difference between normal controls and the patient before the treatment (0M).
iew
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338x190mm (96 x 96 DPI)
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Fo
Figure 5. Analysis of acylceramides in the SC using tape stripped samples. Before the treatment
(0M), CER[EOS], CER[EOH], and CER[EOP] with some carbon chain-lengths were significantly reduced in the
upper arm of the patient. Asterisks (*) under the ceramide classes indicate that there were more than ±2SD
difference between normal control and the patient’s specimens before the treatment (0M). After the oral
etretinate treatment for two months (2M), CER[EOS] with C66:2-70:2 was reduced in the forearm, and was
slightly reduced or almost stable in the upper arm, compared with that before the treatment (0M). On the
other hand, most CER[EOH] and CER[EOP] with C66:2-70:2 was increased after the treatment (2M).
iew
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338x190mm (96 x 96 DPI)
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Murase et al.
Table 1. Significantly upregulated IL-17/TNFα-related genes, psoriasis hallmark
genes and downregulated lipid-associated genes in the patient with a NIPAL4 mutation
compared to the those of healthy individuals
log2Fold change
padj
IL36A
10.11947657
5.02E-18
S100A7A
4.138600176
2.50E-17
VNN3
4.873737416
4.24E-10
IL36G
2.995048792
1.37E-09
S100A9
2.819372931
3.13E-07
LCE3D
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Gene
2.284500298
1.33E-05
4.083101697
0.000137582
2.186189356
0.00025858
Inf
2.66E-10
HAO2
6.279592002
0.001220711
FABP7
2.759705829
0.004124171
upregulated
IL17C
PLA2G4D
downregulated
Abbreviations: Inf, infinite
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Murase et al.
Supplemental Table 1. Expression of differentiation marker genes and causative
genes of congenital ichthyosis in the patient with a NIPAL4 mutation compared to
those of healthy individuals
Gene
log2FoldChange
padj
NIPAL4
0.115011707
CYP4F22
-1.117796124
0.468068081
CERS3
-0.191277747
PNPLA1
-0.598260436
ABCA12
-0.6754053
ALOX12B
-1.049393637
0.633514968
-0.345168445
-0.279500337
-1.412687762
0.165785466
-0.977418757
0.916937625
SLC27A4
-0.505428491
TGM1
-0.974795748
0.82764011
ELOVL1
-0.294565265
ELOVL3
0.947023465
LOR
0.621113868
FLG
1.27192755
0.186598143
PPL
0.547281684
ALOXE3
LIPN
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SDR9C7
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CASP14
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Supplemental Table 2. Significantly upregulated genes in the patient with NIPAL4
mutation compared to those of healthy individuals
Gene
log2FoldChange
padj
SPRR2A
5.076390398
1.18E-26
GSTM1
8.810537168
5.49E-26
SPRR2F
4.717954063
2.36E-21
CCL20
4.765054241
3.05E-21
SPRR2B
4.418554815
1.63E-20
SCD
4.131849204
3.03E-19
IL36A
10.11947657
5.02E-18
S100A7A
4.138600176
2.50E-17
5.204816897
2.01E-14
3.483111428
3.31E-12
3.441103313
7.41E-12
3.230304776
1.71E-10
VNN3
4.873737416
4.24E-10
HEPHL1
3.276580047
7.77E-10
IL36G
2.995048792
1.37E-09
SPRR2D
3.06744172
3.35E-09
LINC00696
3.137019658
5.21E-09
PLIN4
2.997445549
6.10E-09
PAPL
2.978110764
TUSC5
3.020363488
RND1
3.687712299
ACVR1C
3.109820362
SPX
4.212422713
6.71E-08
LCN2
2.968143587
8.14E-08
LCE3C
6.443377197
1.56E-07
LGALS12
3.033460218
1.56E-07
TRHDE-AS1
3.125664479
1.73E-07
CIDEC
2.813003326
1.79E-07
SLC7A10
4.296689505
1.79E-07
CALB2
2.932975498
1.90E-07
KLK9
2.744396246
1.96E-07
PLIN1
2.756173543
2.38E-07
KRT76
RBP4
iew
ev
LIPE
rR
SERPINB3
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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43
44
45
46
47
48
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50
51
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Journal of Dermatological Science
1.04E-08
1.35E-08
2.32E-08
4.41E-08
https://mc.manuscriptcentral.com/jdermscience
Journal of Dermatological Science
Murase et al.
LPL
2.752600145
2.43E-07
S100A9
2.819372931
3.13E-07
NAT8L
2.724932531
6.03E-07
GYG2
2.709075492
1.35E-06
LOC101926960
3.424623138
1.35E-06
FABP4
2.610932229
1.54E-06
PRG4
2.729177443
1.69E-06
PDE3B
2.652724644
2.95E-06
C14orf180
2.766789074
3.47E-06
SLC19A3
2.664220499
3.56E-06
GDA
2.579301475
3.68E-06
3.217526348
3.96E-06
3.570245844
5.67E-06
2.590144454
7.77E-06
2.408879799
9.42E-06
LINC01230
5.284727634
1.09E-05
LCE3D
2.284500298
1.33E-05
IGF1
2.434283761
1.61E-05
FAM65C
2.484483521
1.85E-05
MME
2.478217482
2.02E-05
S100A7
2.499091755
2.14E-05
MMP3
4.13322567
MLXIPL
2.519375249
GLYAT
3.264204912
IGFBP6
2.274281189
CPLX3
3.532971099
3.61E-05
AMPH
2.805185519
3.65E-05
FAAHP1
3.76924588
4.65E-05
GPAM
2.3259428
5.48E-05
ADIPOQ
2.346252698
5.66E-05
SLC29A4
2.510113015
5.66E-05
C17orf96
2.40318415
6.66E-05
GYS2
4.529929425
7.28E-05
GPD1
2.321832158
7.55E-05
FCGR3B
2.484005814
9.82E-05
SLC4A4
S100A8
iew
ev
RNASE7
rR
LCE3A
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
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46
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2.62E-05
2.88E-05
3.11E-05
3.51E-05
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Page 37 of 49
Murase et al.
KCNA1
3.338022861
0.00010015
IL17C
4.083101697
0.000137582
SFRP4
2.504205819
0.00013797
LRRC55
2.789443869
0.00014058
MYOC
2.419221464
0.000190479
TCERG1L
2.743529064
0.000204248
PPP1R1A
2.264263089
0.000215178
TF
2.334896896
0.000215178
NEU2
2.301413833
0.00023794
PLA2G4D
2.186189356
0.00025858
COMP
3.462799218
0.000278846
4.039531923
0.000303984
3.207623604
0.000333882
2.245435578
0.000348861
2.23495182
0.000443921
FASN
2.054398965
0.000715956
PSG7
3.033079198
0.000757267
ABCD2
2.417000512
0.001013948
CILP
1.969622195
0.001034208
DMRT2
2.718112614
0.001034208
MKRN7P
5.092445132
0.001034208
FUT3
2.322187719
SERPINB4
2.240863639
MEST
2.158926927
PKDCC
2.008091227
WFDC12
1.877080247
0.002140251
FCN2
5.064504563
0.00221317
PGLYRP2
3.023393482
0.002346537
FCHSD1
1.921834703
0.002568628
PFKFB1
2.592806523
0.003149877
HRASLS5
2.093257158
0.003553177
FRG2DP
2.933960044
0.003562796
HMOX1
1.882951283
0.003687787
LINC01260
4.249358331
0.003687787
NNAT
2.007339953
0.004150958
IL20
PRSS27
iew
ev
KLB
rR
VGF
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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Journal of Dermatological Science
0.001049253
0.001067071
0.001196111
0.001858284
https://mc.manuscriptcentral.com/jdermscience
Journal of Dermatological Science
Murase et al.
SMOX
1.878904177
0.004150958
ALPK3
2.014565239
0.004449479
B4GALNT2
2.527403396
0.004449479
STOX1
2.164728936
0.004488536
TMC5
1.970744369
0.005036153
SLC37A2
1.823920092
0.00547495
TXLNGY
1.872607344
0.005596214
PRRT4
2.19362745
0.00577426
PDE11A
2.428831892
0.006288599
PRKAR2B
1.847535095
0.00710949
GBAP1
2.280726751
0.008543938
1.779311301
0.009047072
1.712690601
0.009172021
1.790449136
0.009231195
1.841339115
0.009234917
SLC26A9
1.831584663
0.009618955
MSR1
1.944490847
0.010786033
SLC6A14
1.796270977
0.012783386
MRAP
3.077131493
0.013741696
IL36RN
1.677771854
0.014342869
LCE3E
1.652398364
0.014565764
LINC01140
1.845691716
RNF157
2.013430635
ADAMTSL1
1.752928626
CHAC1
2.534319937
VNN1
2.182709826
0.018461334
SPRR1A
1.752708922
0.018584929
RHCG
1.775241772
0.019200472
STAB1
1.657982487
0.019355947
ZBED2
1.844385569
0.019355947
ACKR2
2.055925857
0.01984387
C9orf84
2.090396295
0.020265543
LILRA6
2.582806134
0.020969093
PRSS22
1.858205055
0.020969093
PLA2G16
1.733541212
0.021153509
CD36
PRKY
iew
ev
LILRB5
rR
TNXB
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
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0.016443283
0.016618215
0.017137918
0.018461334
https://mc.manuscriptcentral.com/jdermscience
Page 39 of 49
Murase et al.
RUNDC3A
1.700909386
0.021814569
ADAMTS18
3.143600594
0.026338947
PDK4
1.643288129
0.027088654
KCNIP2
1.780623351
0.029554224
ACACB
1.657267822
0.030856174
HSPB6
1.66264795
0.030898077
TBL1Y
2.985330369
0.030898077
ABCG4
2.492853776
0.031397313
ITIH5
1.618503703
0.034301303
HEPACAM
2.432038966
0.040480955
MMP27
1.753474226
0.04219612
2.189139094
0.042739995
3.170444628
0.043879256
1.543353379
0.044930071
1.660625206
0.044998536
RNF223
1.906880435
0.049468863
LRRN3
2.138109083
0.050874042
CHRNA3
1.969725949
0.050983159
PADI1
1.533350416
0.050983159
MYH15
1.702577333
0.051207238
RORB
2.398215273
0.051207238
ADAMTS9-AS1
3.173815158
ADH1B
1.559721337
MS4A14
2.542541136
ITGA11
1.548220659
SMPD3
1.565815044
0.059630892
LOXL4
1.590922031
0.061245009
AOC3
1.566198281
0.061393059
MEDAG
1.493314453
0.063970458
RGS20
1.595455101
0.068942416
RRM2
1.572109596
0.070493571
CORIN
1.552517353
0.070697251
HTR3A
1.598398746
0.073614871
BLMH
1.513703268
0.079727701
SYNE3
1.534360011
0.083752917
HCAR1
TGM3
iew
ev
FRMPD1
rR
CCDC63
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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Journal of Dermatological Science
0.054502395
0.055026771
0.056074218
0.058355499
https://mc.manuscriptcentral.com/jdermscience
Journal of Dermatological Science
Murase et al.
CCR1
1.614971287
0.08432962
ANKK1
1.564058137
0.093255836
ATP12A
1.626071075
0.093778997
LINC00675
2.143999819
0.096840281
CEMIP
1.517303317
0.09894487
KDM5D
1.453967223
0.09894487
PCOLCE2
1.46284538
0.09894487
iew
ev
rR
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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Murase et al.
Supplemental Table 3. Significantly downregulated genes in the patient with
NIPAL4 mutation compared to those of healthy individuals
log2FoldChange
padj
XIST
11.03125569
3.75E-22
GSTT1
Inf
8.06E-16
PM20D1
7.883136475
2.99E-13
KRT25
9.404434427
7.09E-13
AADACL3
8.797737191
6.22E-11
GAL
Inf
2.66E-10
AWAT2
Inf
1.10E-09
DGAT2L6
8.397554431
1.16E-09
5.064107958
2.15E-08
Inf
3.57E-08
Inf
4.92E-08
7.858251335
5.40E-08
UGT3A2
4.903232732
3.35E-07
FOS
4.368372913
3.93E-07
FOSB
4.332949905
5.29E-07
HRNR
5.167332112
7.53E-07
KRT28
Inf
1.53E-06
KRT75
5.570188963
KRT85
7.217728366
NEFM
6.106788188
ADCYAP1
7.102387153
TECRL
4.88378295
KRT74
4.514297387
2.07E-05
KRT79
3.642419203
3.04E-05
SMG1P3
Inf
3.04E-05
MUC16
5.400665813
3.15E-05
UPK1B
6.967215573
3.15E-05
CA9
5.525227659
0.000115504
KRT27
3.780199306
0.000118872
WDR72
3.61342521
0.000136124
FABP9
Inf
0.000167104
BTC
3.525932805
0.000177101
TCHH
HORMAD1
SLC44A5
iew
ev
AWAT1
rR
Gene
Fo
3.07E-06
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Journal of Dermatological Science
4.35E-06
9.42E-06
1.38E-05
1.42E-05
https://mc.manuscriptcentral.com/jdermscience
Journal of Dermatological Science
Murase et al.
KRT35
6.585542034
0.000215178
COMP
3.462799218
0.000278846
FREM2
4.050653386
0.000384183
OBP2B
6.495354719
0.000402582
CHURC1
3.158443705
0.00054045
AGR2
3.882528333
0.000650907
NEFL
3.896556359
0.001034208
HAO2
6.279592002
0.001220711
CYP4B1
2.894373067
0.001225161
CXCL10
3.73487792
0.001339047
AGR3
5.001691368
0.001948622
6.186173593
0.002053744
Inf
0.002441908
2.763505924
0.003120642
Inf
0.003404942
CEACAM6
2.779414579
0.003581416
FABP7
2.759705829
0.004124171
TNNI2
2.809762506
0.004270725
CACNA1H
2.711200019
0.004273195
SPRR4
2.623862049
0.004521204
STC1
2.913881653
0.004915589
NELL2
2.872245545
CHRM4
3.059877509
LIPG
3.133148843
PRR4
3.888067773
KRT6B
2.577249742
0.006828266
CXCL9
2.84829812
0.009015826
BEST2
3.6216481
0.009434952
ABCA4
3.683262766
0.009618955
ABCB5
3.355534722
0.009661772
DUSP1
2.448124626
0.010943098
HLA-DRB5
2.719452126
0.011908283
LHX2
3.370298835
0.012783386
WFDC2
3.029675572
0.013588143
GLDC
4.947013584
0.017452473
EDN2
IGLL5
iew
ev
SYCE1
rR
ROS1
Fo
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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46
47
48
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50
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0.005036153
0.005059202
0.00547495
0.006718174
https://mc.manuscriptcentral.com/jdermscience
Page 43 of 49
10
Murase et al.
HLA-DRB6
4.202413348
0.018461334
SOCS3
2.331416864
0.019355947
PRR9
2.743541014
0.021909727
MAT1A
2.6500361
0.02231531
CYP2W1
2.546148966
0.025471391
CCL18
2.589539227
0.030898077
XKR9
Inf
0.035719224
SLC9A2
2.48815397
0.035731963
FLJ42627
Inf
0.035918583
KLHDC7B
2.976518118
0.037354393
GPR12
2.241012926
0.043657573
2.99912115
0.044685874
2.240381618
0.046035529
2.129467356
0.048599828
2.934416108
0.050910302
RGS1
2.311461745
0.051207238
KRT6A
2.13308146
0.054920768
WNT2
2.516181178
0.056294032
IFI44L
2.000668488
0.058550645
KRT26
Inf
0.061066337
GATA3-AS1
2.562277593
MZB1
4.605592086
LINC01229
2.997994006
CFTR
2.182591824
NOTUM
2.486535617
LOC391322
Inf
0.080816203
KRT9
2.304255733
0.082142545
HERC6
1.933692638
0.089457114
POSTN
2.024938452
0.089457114
TMEM63C
2.667561067
0.093265091
OAS2
1.902831337
0.09337669
ATF3
1.983386763
0.093880525
PMP2
2.503093909
0.094887401
SERPINA9
PHYHIP
iew
ev
SPINK7
rR
SLC34A2
Fo
0.061074606
ly
On
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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Journal of Dermatological Science
0.061978477
0. ...
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