Genetic and Proteomic Contributions to the Pathophysiology of Moyamoya Angiopathy and Related Vascular Diseases

Figures & data

Table 1 Chromosomes and Genetic Defects Related to Moyamoya Angiopathy

Chromosome	Genetic Defects—Factors Affecting:
	Vascular Stenosis*	Aberrant Angiogenesis†	Vascular Stenosis and Aberrant Angiogenesis
Chromosome1^Citation4^–^Citation6,Citation16^–^Citation37	1p36.22 MTHFR (677C>T, C677T/A1298C, rs9651118); 1p31.3 ROR1; 1p13.3 PSRC1 (rs599839 [A/G]); 1q42.13 OBSCN	1p34.2 TIE1; 1p21.2 VCAM1; 1q24.2 SELE	1p13.2 NRAS: Noonan syndrome; 1p12-p11 NOTCH2: Alagille syndrome; 1q21.3 S100A4
Chromosome2^Citation4,Citation5,Citation20,Citation35,Citation38,Citation39	2q14.1 IL1B	2q24.2 GCG, Oxyntomodulin (P01275)	2p22.1 SOS1: Noonan syndrome
Chromosome3^Citation4,Citation21,Citation35,Citation36,Citation38,Citation40^–^Citation43	3q21.3 ZXDC (p.P562L)	3p26-p24.2 MYMY1 (D3S3050): von Hippel-Lindau disease, Marfan syndrome; 3p22.1 CTNNB1; 3p21.31 CAMP, antibacterial protein LL-37 (P49913); 3p21.31 UCN2, urocortin-2 (Q96RP3); 3q22.2 CEP63: Seckel syndrome; 3q23 ATR: Seckel syndrome	3p25.2 RAF1: Noonan syndrome
Chromosome4^Citation4,Citation5,Citation20,Citation44^–^Citation47		4q32.1 GUCY1A3 or GUCY1A1, sGCα1ß1 loss, sGCα2ß1 residual	4q28.1 FGF2
Chromosome5^Citation21,Citation38,Citation48^–^Citation50		5q31.1 LEAP2, liver-expressed antimicrobial peptide 2 (Q969E1)	5q14.3 EDIL3; 5q32 PDGFRB (rs3828610 [A/C])
Chromosome6^Citation1,Citation5,Citation6,Citation16,Citation20,Citation38,Citation51^–^Citation58		6p21.1 VEGFA (VEGF-634C); 6p12.3 DEFB133, beta-defensin 133 (Q30KQ1)	6p22.1 HLA-A; 6p21.33 HLA-B; 6p21.32 HLA-DRA; 6p21.32 HLA-DRB1 (DRB1*1510, DRB1*03, DRB1*13, DRB1*1302); 6p21.32 HLA-DQA1 (DQA1*01021); 6p21.32 HLA-DQA2; 6p21.32 HLA-DQB1 (DQB1*0502, DQB1*0620, DQB1*0609); 6q25 (D6S441); 6q25.1 ULBP3
Chromosome7^Citation4^–^Citation6,Citation17,Citation35,Citation37,Citation59^–^Citation67	7p21.1 HDAC9 (rs2107595); 7q11.23 ELN (rs34208922 [−/A], rs8326 [C/G])	7p15.3 IL6	7q21.11 HGF; 7q31.2 CAV1; 7q34 BRAF: Noonan syndrome; 7q36.1 NOS3 (a-4b-G haplotype)
Chromosome8^Citation24,Citation38,Citation52,Citation53,Citation68,Citation69		8p23.1 ANGPT2; 8q12.1 PENK, proenkephalin-A (143–183) (P01210); 8q23.1 ANGPT1	8q22.3 KLF10; 8q22.3 UBR5; 8q23 (D8S546); 8q23.2 EBAG9
Chromosome9^Citation24,Citation59,Citation70^–^Citation72	9q34.11 ENG	9p21.2 TEK or TIE2
Chromosome 10^Citation2,Citation4,Citation6,Citation16,Citation19,Citation73^–^Citation77	10q23.31 ACTA2 (R179, p.R258C/H)	10q11.21 CXCL12 (rs501120 [A/G])
Chromosome 11^Citation3^–^Citation5,Citation20,Citation78^–^Citation85	11p15.4 HBB: sickle cell disease; 11q22.2 MMP3 (–1171 5A/6A (rs3025058)); 11q22.2 MMP12		11p15.5 HRAS: Costello syndrome
Chromosome 12^Citation4,Citation35,Citation52,Citation68,Citation85,Citation86			12p12.1 KRAS: Noonan syndrome, Costello syndrome; 12p12 (D12S1690); 12q24.13 PTPN11, hyperactive SHP-2: Noonan syndrome
Chromosome 13^Citation4,Citation42,Citation43,Citation87,Citation88		13q12.12-q12.13 CENPJ: Seckel syndrome; 13q14.11 FOXO1, nuclear forkhead box protein O1
Chromosome 14^Citation4,Citation18,Citation42,Citation43,Citation59,Citation70,Citation71,Citation89	14q23.2 HIF1A; 14q32.13 SERPINA1	14q22.1 NIN: Seckel syndrome	14q32.33 IGHG1, immunoglobulin heavy constant gamma 1
Chromosome 15^Citation4,Citation16,Citation35,Citation42,Citation43,Citation90^–^Citation92		15q21.1 CEP152: Seckel syndrome	15q21.3 ALDH1A2; 15q22.31 MAP2K1: Noonan syndrome; 15q25.1 CRABP1
Chromosome 16^Citation6		16q12.2 MMP2 (MMP-2-1575GA/-1306CC)
Chromosome 17^Citation2,Citation4,Citation6,Citation9,Citation19^–^Citation21,Citation37,Citation48,Citation53,Citation74,Citation93^–^Citation105	17q11.2 NF1: Neurofibromatosis type I; 17q25.3 CENPX; 17q25.3 GPS1; 17q25.3 TIMP2 (heterozygous TIMP-2-418 (rs8179090 [G/C]))	17q12 CCL2; 17q12 CCL5; 17q25.3 BAIAP2; 17q25.3 RNF213 (c.14576G>A, rs9916351, rs112735431, rs148731719, p.R4859K, p.R4810K); 17q25.3 RPTOR (ss161110142 [G/A])	17q25 (D17S939; 9-cM region between D17S785 and D17S836); 17q25.3 (D17S704; candidate interval 3.5Mb between D17S1806 and the telomere of 17q)
Chromosome 18^Citation4,Citation42,Citation43		18q11.2 RBBP8: Seckel syndrome
Chromosome 19^Citation5,Citation9,Citation16,Citation17,Citation20,Citation74,Citation106^–^Citation114	19p13.3 PRTN3	19p13.2 ICAM1	19q13.2 TGFB1 (rs1800471 [C/G])
Chromosome 20^Citation4,Citation6,Citation25^–^Citation34,Citation74		20q11.3 SAMHD1	20p12.2 JAG1: Alagille syndrome; 20q13.12 MMP9 (dominant type (GG vs GA+AA) of MMP-9 Q279R (rs17576))
Chromosome 21^Citation4,Citation21,Citation42,Citation43,Citation115,Citation116	21q21.3 APP	21q22.13 DSCR3: Down syndrome (trisomy 21); 21q22.3 PCNT: MOPDII, Seckel syndrome
Chromosome 22^Citation20,Citation37,Citation108,Citation117,Citation118	22q12.2 TCN2 (rs117353193)		22q13.1 PDGFB
ChromosomeX^Citation4,Citation6,Citation20,Citation119	Xp11.3 TIMP1	Xq28 BRCC3/MTCP1

Notes: *Vascular stenosis includes intimal thickening, media attenuation, and internal elastic lamina damage. †Aberrant angiogenesis includes capillary sprouting.

Abbreviations: See Supplemental Data.

Table 2 Molecular Biomarkers of Moyamoya Angiopathy by Protein Class

Biomarker	Level in Moyamoya Angiopathy:
	Increased	Increase Suspected	Decreased
Enzymes
Alpha-1 antitrypsin^Citation89*	✓
MMP-2^Citation6,†	✓
MMP-3^Citation5,Citation20,Citation78,Citation79*			✓
MMP-9^Citation5,Citation6,Citation15,Citation20,Citation39,Citation52,Citation54,Citation121^–^Citation123,‡	✓
MMP-12^Citation20*	✓
TIMP-1, −2^Citation6,Citation20*			✓
MTHFR^Citation6*	✓
RALDH2^Citation16,Citation90,‡			✓
eNOS^Citation6,‡	✓
Growth factors
VEGF^Citation5,Citation6,Citation16,Citation20,Citation54^–^Citation56,†	✓
Endoglin^Citation59,Citation70,Citation71*	✓
PDGF-BB^Citation20,Citation108,Citation117,Citation118,‡	✓
HGF^Citation5,Citation63,Citation65^–^Citation67,‡	✓
bFGF^Citation5,Citation20,Citation45^–^Citation47,‡	✓
TGF-β^Citation5,Citation9,Citation17,Citation108^–^Citation114,‡	✓
ANG(PT)/Tie^Citation24,Citation56,Citation68,Citation69,Citation87,Citation88,Citation124^–^Citation129,†		✓
Caveolin-1^Citation16,Citation76,Citation130^–^Citation133,‡			✓
EPCs^Citation2,Citation5,Citation16,Citation77,Citation134^–^Citation140,‡	✓(adult MA)		✓(pediatric MA)
Smooth muscle progenitor cells^Citation2,Citation16,Citation135,Citation141,†		✓
Transcription factors
HIF-1α^Citation59,Citation70,Citation71*	✓
Adhesion molecules
VCAM-1^Citation5,Citation16,Citation20,†	✓
ICAM-1^Citation5,Citation16,Citation20,†	✓
E-selectin^Citation5,Citation16,Citation20,†	✓
CRABP1^Citation16,Citation91,Citation92,‡	✓
Inflammation/coagulation
MCP-1^Citation20,†	✓
IL-1β^Citation5,Citation20,Citation39*	✓
IL-6^Citation60^–^Citation64,†	✓
p-ANCA^Citation106*	✓
D-dimer^Citation142*	✓
SDF-1α^Citation76,Citation77,†	✓
CCL5^Citation143,Citation144,†	✓
Immune-related factors/autoantibodies
S100A4 protein and immunoglobulinG^Citation18,Citation19,‡		✓
Anti-alpha-fodrin autoantibodies^Citation145*		✓
APP^Citation21,Citation115*	✓
Catenin beta-1^Citation21,†	✓
EDIL3^Citation21,Citation49,Citation50,‡	✓
ROR1^Citation21^–^Citation23*	✓
GPS1^Citation21*	✓
STRA13^Citation21*	✓
Biomarker candidates
Gla-42 transthyretin^Citation146*	✓
Complement C1 inhibitor protein^Citation147*	✓
Apolipoprotein C-III^Citation147*			✓
Apolipoprotein-E^Citation148*			✓
Apolipoprotein E precursor^Citation148*			✓
Apolipoprotein-J^Citation148*			✓
Alpha-1-B-glycoprotein^Citation148*	✓
Oxyntomodulin (P01275)^Citation38,†		✓
Urocortin-2 (Q96RP3)^Citation38,†		✓
Beta-defensin 133 (Q30KQ1)^Citation38,†		✓
Antibacterial protein LL-37 (P49913)^Citation38,†		✓
Liver-expressed antimicrobial peptide 2 (Q969E1)^Citation38,†		✓
Proenkephalin-A (143–183) (P01210)^Citation38,†		✓
4473Da^Citation2,Citation149,†	✓
Haptoglobin^Citation148,†	✓

Notes: *Indicates that the factor affects vascular stenosis (intimal thickening, media attenuation, and internal elastic lamina damage). ^†Indicates that the factor affects aberrant angiogenesis (capillary sprouting). ^‡Indicates that the factor affects both vascular stenosis and aberrant angiogenesis.

Abbreviations: See Supplemental Data.

Figure 1 Potential disease mechanisms in MA. Red indicates that the factor affects vascular stenosis (intimal thickening, media attenuation, and internal elastic lamina damage). Blue indicates that the factor affects aberrant angiogenesis (capillary sprouting). Green indicates that the factor affects both vascular stenosis and aberrant angiogenesis.

Notes: Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Abbreviations: See Supplemental Data.

Figure 2 Proteins, cells, genes, and signaling pathways related to cerebral angiopathy characteristics in MA and associated disorders. (A) Arteriovenous malformation. (B) Intracranial aneurysm. (C) Vascular/internal carotid artery stenosis. (D) Stroke. Red indicates that the factor affects vascular stenosis (intimal thickening, media attenuation, and internal elastic lamina damage). Blue indicates that the factor affects aberrant angiogenesis (capillary sprouting). Green indicates that the factor affects both vascular stenosis and aberrant angiogenesis.

Notes: Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Abbreviations: See Supplemental Data.

Figure 3 Schematic representation of an artery depicting macroscopic active sites of proteins, signaling pathways, genes, and cells in MA and associated disorders. Red indicates that the factor affects vascular stenosis (intimal thickening, media attenuation, and internal elastic lamina damage). Blue indicates that the factor affects aberrant angiogenesis (capillary sprouting). Green indicates that the factor affects both vascular stenosis and aberrant angiogenesis.

Notes: Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Abbreviations: See Supplemental Data.

Figure 4 Microscopic active sites of proteins, cells, genes, and signaling pathways in MA and associated disorders. (A) Bone marrow. (B) Blood/immune system. (C) Cerebrospinal fluid. Red indicates that the factor affects vascular stenosis (intimal thickening, media attenuation, and internal elastic lamina damage). Blue indicates that the factor affects aberrant angiogenesis (capillary sprouting). Green indicates that the factor affects both vascular stenosis and aberrant angiogenesis.

Notes: Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Abbreviations: See Supplemental Data.

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