Dissection of Z-disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach

Table 1 The disease enrichment analysis

Disease	Gene No.	Adjusted value
Cardiovascular diseases	59	4.38E-05
Heart diseases	50	0.0002
Vascular diseases	49	0.0003
Cardiovascular abnormalities	27	0.0003
Bradycardia	9	0.0067
congenital long QT syndrome	6	0.0094
Metaplasia	26	0.0094
Cerebrovascular disorders	25	0.0094
Arrhythmias, cardiac	19	0.0094
Syncope	12	0.0094
Romano-ward syndrome	6	0.0094
Neovascularization, pathologic	24	0.0094
Atrial fibrillation	14	0.0094
Glycogen storage disease	8	0.0097
Myocardial ischemia	34	0.0097
Glycogen storage disease, type IV	5	0.0181
Heart murmurs	4	0.0207
Congenital abnormalities	61	0.0207
Adhesion	64	0.0207
Heart defects, congenital	17	0.0207
Ventricular dysfunction	14	0.0207
Atrioventricular block nitrous oxide system	8	0.0264
Heart block	11	0.0315
Parkinson disease	18	0.0450
Mesothelioma	10	0.0450
Coronary artery disease	31	0.0450
Stress	50	0.0450
Coronary disease	31	0.0450
Jervell-lange nielsen syndrome	4	0.0450

Table 2 The significantly enriched gene pathways

Pathway name	No. Gene	Adjusted value
Insulin signaling pathway	28	9.47E-06
Endocytosis	33	0.0003
Hypertrophic cardiomyopathy	15	0.0171
Arrhythmogenic right ventricular cardiomyopathy	13	0.0385
Extracellular matrix-receptor interaction	14	0.0445
Focal adhesion	24	0.0462
Prostate cancer	14	0.0462
Tryptophan metabolism	9	0.0462
Pathways in cancer	35	0.0462
MAPK signaling pathway	30	0.0462

MAPK: Mitogen-activated protein kinase.

Table 3 Differentially expressed proteins identified by MALDI MS-MS

No.	Protein code	Gene ID	KI/WT	KO/WT	KO/KI	Pathways
1	PKP1	18772	1.76	-1.13	-1.99	Focal adhesion, apoptosis
2	HRC	15464	1.62	1.06	-1.53	Calcium signaling
4	PYGB	53313	1.61	1.16	-1.39	Glucagon signaling, insulin signaling
5	MSN1	17698	-2.68	4.71	12.57	Cell shape, actin-cytoskeleton
6	VINC	22330	-4.18	4.96	20.64	Cell-cell adhesion, cell shape, actin cytoskeleton
8	SYNE11	64009	-3.59	5.82	20.82	Nucleus-cytoskeleton connection
14	ADAM10	11487	1.71	-1.18	-2.02	Inflammation, amiloidosis
17	TNPO3	320938	-1.11	1.51	1.67	Nucleus-cytoskeleton connection
18	CAPN8	170725	2.15	-1.02	-2.19	Inflammation
19	CGNL1	68178	1.58	-1.03	-1.63	Focal adhesion
20	VIM	22352	1.43	1.40	-1.02	Cell division, fibrosis
23	MYH6	17888	1.02	-3.41	-3.49	Sarcomere, actin-cytoskeleton
24	NRAP	18175	-1.03	1.79	1.84	Focal adhesion, actin cytoskeleton
28	ANXA3	20480	1.23	-1.80	-2.23	Prostaglandin synthesis and regulation
29	LATS2	23805	-1.58	-1.51	1.04	Hippo signaling pathway, DNA damage
32	SPTB1	20741	1.56	-1.01	-1.59	Actin-cytoskeleton
33	GCC2	11426	1.04	-3.78	-3.92	Vesicle-mediated transport, retrograde transport at the trans-Golgi-network
37	ACADS	12306	-2.01	1.12	2.24	Mitochondrial fatty acid beta-oxidation
39	FHL2	14200	1.05	-2.25	-2.37	Focal adhesion, Wnt, calcineurin signaling
39	MYOZ2	59006	1.05	-2.25	-2.37	Cytoskeleton, calcineurin signaling, myofibrillogenesis
47	FGF9	14180	2.93	5.90	2.01	Fibrosis
53	DST	13518	2.23	1.01	-2.21	Focal adhesion, actin cytoskeleton
59	FEZ2	56069	1.89	-1.11	-2.12	N/A
59	CSRP3	13009	1.89	-1.11	-2.12	Stress sensing, myogenesis
62	MYOM1	319565	-1.37	1.58	2.15	Striated muscle contraction
63	MYOM2	17930			+++	Sarcomere
65	EZR/MSN	17698			+++	Cell surface organization, adhesion, microtubule

¹Genes with statistically significant correlation with that of Mypn in mouse hearts. KI: Knock-in Mypn mouse; KO: Knock-out Mypn mouse; WT: Wild type littermates; -: Proteins downregulated compared to WT; +++: Proteins with differentially phosphorylated proteins in KI vs KO; N/A: Not applicable.

Table 4 Genes whose gene expression has significant correlation with Mypn and gene product have significant change comparing with KI or KO mice

Protein code	Corr P value	KI/WT	KO/WT	KO/KI
CGNL1	0.0024	1.58	-1.03	-1.63
PKP1	0.0082	1.76	-1.13	-1.99
SYNE11	0.0114	-3.59	5.82	20.82
PYGB	0.0157	1.61	1.16	-1.39
MSN	0.0194	-2.68	4.71	12.57
ANXA3	0.0319	1.23	-1.8	-2.23
MYOM11	0.0335	-1.37	1.58	2.15
ACADS	0.035	-2.01	1.12	2.24
GCC2	0.0375	1.04	-3.78	-3.92
FEZ2	0.0399	1.89	-1.11	-2.12
LATS2	0.0431	-1.58	-1.51	1.04

¹Genes with statistically significant correlation with that of Mypn in mouse hearts. KI: Knock-in Mypn mouse; KO: Knock-out Mypn mouse; WT: Wild type littermates; -: Proteins downregulated compared to WT.