Table 1 Differentially expressed genes in affected plantar hyperkeratosic skin of RSPO1-mutated patient vs plantar control clustered into biological processes

Intermediate filament bundle assembly

4/7

10.51

1.74E-03

2.98E-02

NEF3, NEFL

PKP2, EPPK1

Hemidesmosome assembly

7/12

9.19

2.02E-04

5.16E-03

ITGB4,LAMC1,LAMC2,BPAG1 (DST), COL17A1,CD151

LAMB3

Collagen-activated tyrosine kinase receptor signaling pathway

6/12

9.19

2.02E-04

5.16E-03

COL1A1,COL4A5,COL4A2,COL4A1, COL4A6

DDR1

Basement membrane assembly

5/10

9.19

7.04E-04

1.44E-02

LAMB1, PLOD3, LAMB2, PRG2 (PXDN)

LAMB3

Regulation of transforming growth factor beta activation

4/8

9.19

2.50E-03

4.01E-02

LTBP1, ITGAV

ITGB6, ITGB8

Desmosome organization

6/10

9.19

7.04E-04

1.44E-02

SNAI2

PKP2, PKP3, JUP, LBP-32 (GRHL1), PIGPC1(PERP)

Regulation of keratinocyte migration

6/14

7.88

3.86E-04

8.75E-03

HAS2, MAP4K4

MAPRE2, EPB41L4B, MMP9, EPPK1

Positive regulation of keratinocyte migration

5/12

7.66

1.33E-03

2.40E-02

HAS2, MAP4K4

MAPRE2, EPB41L4B, MMP9

Collagen-activated signaling pathway

6/15

7.35

5.16E-04

1.12E-02

COL1A1,COL4A5,COL4A2, COL4A1, COL4A6

DDR1

Basement membrane organization

11/28

7.22

2.89E-06

1.29E-04

PLOD3,LAMC2,NID1,FLRT2,COL4A1, LAMB1, EXT1, CAV1, LAMB2, PRG2 (PXDN)

DAG1

Regulation of extracellular matrix disassembly

6/16

6.90

6.79E-04

1.41E-02

IL6, TGFB1, FSCN1,LRP1, ETS1

DDR1

Regulation of extracellular matrix assembly

5/14

6.57

2.29E-03

3.74E-02

TGFB1, TEM8, HAS2,

DAG1, SOX9

Negative regulation of keratinocyte proliferation

5/14

6.57

2.29E-03

3.73E-02

KLF9 (BTEB1), EFNB2, CD109, SNAI2

EPPK1

Positive regulation of keratinocyte differentiation

6/18

6.13

1.12E-03

2.09E-02

CYP27B1, ALOX15B, NCOA3,

PRKCH, TRIM16, FOXC1

Extracellular matrix assembly

10/32

5.75

4.16E-05

1.35E-03

TGFB1, LOX, LAMB1, PLOD3, HAS2, LAMB2, PRG2 (PXDN), EFEMP2

HAS3, LAMB3

Heterotypic cell–cell adhesion

11/36

5.62

2.05E-05

7.29E-04

ITGAV, ITGA5, PARVA, CD1D, CD58, JAM3

PKP2, DSC2, JUP, PIGPC1 (PERP), CXADR

Collagen fibril organization

15/50

5.52

8.09E-07

4.01E-05

P4HA1, SERPINH1, LOX, COL5A3, COL1A1, CRTAP, EXT1, PLOD3, TGFBR1, PRG2 (PXDN), LOXL2, COL3A1, COL5A2, COL5A1

FOXC1

Regulation of bicellular tight junction assembly

7/24

5.36

8.42E-04

1.66E-02

IKBKB, SNAI2, RUNX1

EPHA2, PRKCH, CLDN1, TJP1 (ZO-1)

Substrate adhesion-dependent cell spreading

16/56

5.25

6.05E-07

3.05E-05

PIK3R1, NRP1, PLEKHC1, BVES, LAMB1, LAMC1, LPXN, TEM8, PARVA, AXL, PXN, LAMB2, FER, ITGAV

LAMB3, FN1,

Cell adhesion mediated by integrin

7/25

5.15

1.03E-03

1.96E-02

ITGA5, ITGB4, ADAM17, FBN1, ITGAV

ITGB6, ITGB8

Establishment of skin barrier

7/25

5.15

1.03E-03

1.96E-02

MET

KRT16, CLDN1, UGCG, ABCA12, FAAH, KRT1

Positive regulation of transforming growth factor beta receptor signaling pathway

8/29

5.07

4.95E-04

1.08E-02

TGFB1I1, THBS1, ADAM17

CDKN2B, CITED2, RGS19IP1, GOT1, CDKN1C

Positive regulation of extracellular matrix organization

6/22

5.01

2.63E-03

4.18E-02

IL6, TGFB1, FSCN1,

SOX9, CFLAR, DAG1

Positive regulation of epithelial to mesenchymal transition

13/48

4.98

1.11E-05

4.35E-04

IL6, TGFB1,COL1A1,TGFBR2,TGFBR1, PLEKHC1, NMA, LOXL2,TGFB1I1

SERPINB3, TIAM1, TCF7L2, FOXC1

Regulation of extracellular matrix organization

11/42

4.82

6.77E-05

2.03E-03

IL6, TGFB1,LRP1,HAS2, FSCN1, ETS1, TEM8

SOX9, DAG1, DDR1, CFLAR

Positive regulation of epidermis development

8/31

4.75

7.19E-04

1.47E-02

CYP27B1, ALOX15B, NCOA3,

PPARD, PRKCH, KRT10, TRIM16, FOXC1

Regulation of keratinocyte differentiation

11/42

4.38

2.80E-04

6.73E-03

CYP27B1,TP63,CD109, RUNX1, NCOA3,ALOX15B

AQP3, PRKCH, SERPINB13, FOXC1, TRIM16

Regulation of transforming growth factor beta production

9/38

4.35

5.79E-04

1.23E-02

ATF2, LTBP1, THBS1, FBLN1, ITGAV

ITGB6, ITGB8, FN1, CD24

Positive regulation of epithelial cell migration

36/152

4.35

7.35E-12

8.64E-10

ITGA3, TGFB1, SPARC, THBS1, AKT3, WNT5A, NRP1, RRAS,ARHB, HAS2, ADAM17, CALR, TGFBR2, MAP4K4, HBP17, ETS1, VEGFC, PKD2, MET, GRN

CTSH, SOX9, HSPB1, RAB11A, ANXA3, PIK3C2A, RAB25, MMP9,EPB41L4B, ANXA1, EDN1, FGF1, MAPRE2, PIK3CB, SNK, EGF

Extracellular matrix organization

85/363

4.31

5.46E-26

3.77E-23

P4HA1, TNC, ITGA5, TGFB1, MMP28, ITGB4, SERPINH1, COL27A1, COL4A6, SERPINE1, LOX, COL5A3, LAMB1, COL6A3, LAMC1, PTX3, COL4A5, COL1A1, TIMP1, CRTAP, APP, NID1, URB, EXT1, COL6A2, FBN2, HSPG2, PLOD3, THBS1, TGFBR1, HAS2, COL4A1, ITGA3, DCN, CAV1, LAMB2, CD44, COL7A1, LAMC2, BMP1, COL6A1, PRSS11, PRG2 (PXDN), LOXL2, FLRT2, ST7, EFEMP2, COL3A1, COL4A2, TGFBI, JAM3, SPARC, CAPNS2, COL5A2, FGG, FBN1, FBLN1, ITGAV, COL17A1, MMP14, COL5A1, MMP2

CDH1, ITGB6, ITGB8, DAG1, KLK7, SOX9, MMP9, LAMB3, FN1, SPINK5, DDR1, KLK5, FOXC1, HAS3, CSPG2, MMP10, DNAJB6, TIMP2, CTGF, SULF2, MAGP2, SPINT1, BIGM103

Cell-substrate junction assembly

10/43

4.28

3.29E-04

7.65E-03

ITGA5, PLEKHC1, CD151, ITGB4, LAMC1, LAMC2, COL17A1

LAMB3, FN1, ARHD

Regulation of epidermis development

15/69

4.00

2.30E-05

8.07E-04

DLL1, CYP27B1, ALOX15B, NCOA3, CD109, RUNX1

PRKCH, KRT10, SERPINB13, AQP3, TRIM16, FOXC1, HES1, MAFF, PPARD

Cornification

24/113

3.91

1.33E-07

7.62E-06

JUP, KLK13, KRT6B, SPRR2B, PKP2, TGM1, PKP3, KRT16, SPRR1B, KRT10, DSC1, IVL, PPL, KRT15, PI3, PIGPC1, DSC2, SPRR3, K6HF, KRT1, DSG1, SPINK5, DSG3, KLK5

Negative regulation of cell–matrix adhesion

8/38

3.87

2.22E-03

3.65E-02

PIK3R1, SERPINE1, THBS1, LRP1, CDKN2A, MAP4K4, MMP14

RASA1

Regulation of epidermal cell differentiation

13/62

3.86

1.10E-04

3.09E-03

DLL1, CYP27B1, ALOX15B, NCOA3, CD109, RUNX1

PRKCH, HES1, MAFF, SERPINB13, AQP3, TRIM16, FOXC1

Negative regulation of cell-substrate adhesion

13/63

3.79

1.26E-04

3.49E-03

PIK3R1, SERPINE1, COL1A1, THBS1, LRP1, CDKN2A, MAP4K4, FBLN1, MMP14, LGALS1

TACSTD2, RASA1, GBP1

Extracellular matrix disassembly

13/66

3.62

1.89E-04

4.89E-03

LAMC1, TIMP1, CD44, BMP1, PRSS11, CAPNS2, MMP14, MMP2

KLK7, MMP9, TIMP2, MMP10, KLK5

Keratinocyte differentiation

34/269

2.32

2.00E-05

7.13E-04

TXNIP, WNT5A, PSAP

EPHA2, JUP, KLK13, IRF6, KRT6B, SPRR2B, PKP2, TGM1, PI3, PKP3, KRT16, ASAH1, SPRR1B, KRT10, S100A7, DSC1, IVL, UGCG, PPL, KRT15, PIGPC1, DSC2, ABCA12, SPRR3, K6HF, KRT1, DSG1,SPINK5, DSG3, KLK5, ANXA1

Cell junction organization

61/491

2.28

2.35E-08

1.55E-06

TNC, GJB2, ITGA5, TGFB1, PRNP, NFIA, NRP1, PLEKHC1, CD151, ITGB4, RAB7L1, DNER, LAMC1, COL4A5, APP, DBN1, EXT1, VMP1, WNT5A, SYNPO, FSCN1, COL4A1, ITGA3, LAMB2, PCDHGC3, MAP1B, LAMC2, FLNA, JAM3,, NEDD, SNAI2, WRB, NEFL, COL17A1, PAK2

CXADR, JUP, CDH1, PKP2, POF1B, IL1RAP, PKP3, SPTBN2, INADL, EFNB2, CLDN1, TRAD, ARHD, KLK8, PTPRF, LNIR, PIGPC1, CAST, F2RL1, UNC13, LAMB3, DKK1, DSG1, TJP1, PRKCI