Abstract
Targeted gene disruption in mice has provided valuable insights into the functions of matricellular proteins. Apart from missense and loss of function mutations that have been associated with inherited diseases, however, their functions in humans remain unclear. The availability of deep exome sequencing data from over 140,000 individuals in the Genome Aggregation Database provided an opportunity to examine intolerance to loss of function and missense mutations in human matricellular genes. The probability of loss-of-function intolerance (pLI) differed widely within members of the thrombospondin, CYR61/CTGF/NOV (CCN), tenascin, small integrin-binding ligand N-linked glycoproteins (SIBLING), and secreted protein, acidic and rich in cysteine (SPARC) gene families. Notably, pLI values in humans had limited correlation with viability of the corresponding homozygous null mice. Among the thrombospondins, only THBS1 was highly loss-intolerant (pLI = 1). In contrast, Thbs1 is not essential for viability in mice. Several known thrombospondin-1 receptors were similarly loss-intolerant, although thrombospondin-1 is not the exclusive ligand for some of these receptors. The frequencies of missense mutations in THBS1 and the gene encoding its signaling receptor CD47 indicated conservation of some residues implicated in specific receptor binding. Deficits in missense mutations were also observed for other thrombospondin genes and for SPARC, SPOCK1, SPOCK2, TNR, and DSPP. The intolerance of THBS1 to loss of function in humans and elevated pLI values for THBS2, SPARC, SPOCK1, TNR, and CCN1 support important functions for these matricellular protein genes in humans, some of which may relate to functions in reproduction or responding to environmental stresses.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and materials
All data is contained in the manuscript or the indicated public databases.
Abbreviations
- α2δ1:
-
Precursor of the α2 and δ subunits of voltage-dependent calcium channel, encoded by CACN2D1
- CCN:
-
Cyr61/CTGF/NOV gene family
- CD148:
-
Membrane-bound tyrosine phosphatase, encoded by PTPRJ
- COMP:
-
Cartilage oligomeric matrix protein
- DMP1:
-
Dentin matrix protein 1
- DSPP:
-
Dentin sialophosphoglycoprotein
- ExAC:
-
Exome Aggregation Consortium
- gnomAD:
-
Genome Aggregation Database
- IBSP:
-
Bone sialoprotein
- LoF:
-
Loss of function
- LRP1:
-
Low density lipoprotein receptor-related protein 1
- MEPE:
-
Matrix extracellular phosphoglycoprotein
- pLI:
-
Probability of loss-of-function intolerance
- SIBLING:
-
Small integrin-binding ligand N-linked glycoproteins
- SIRPα:
-
Signal regulatory protein-α
- SMOC:
-
Secreted modular calcium-binding protein
- SNV:
-
Single nucleotide variation
- SPARC:
-
Secreted protein, acidic and rich in cysteine
- SPOCK:
-
Sparc/osteonectin, CWCV, and kazal-like domains proteoglycan (Testican)
- SPP1:
-
Osteopontin
- STIM1:
-
Stromal interaction molecule 1
- THBS:
-
Thrombospondin
- TN:
-
Tenascin
References
Abouzeid H et al (2011) Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome. Am J Hum Genet 88:92–98. https://doi.org/10.1016/j.ajhg.2010.12.002
Agah A, Kyriakides TR, Lawler J, Bornstein P (2002) The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol 161:831–839. https://doi.org/10.1016/s0002-9440(10)64243-5
Ambily A et al (2014) The role of plasma membrane STIM1 and Ca(2+)entry in platelet aggregation. STIM1 binds to novel proteins in human platelets. Cell Signal 26:502–511. https://doi.org/10.1016/j.cellsig.2013.11.025
Arun A et al (2020) Thrombospondin-1 plays an essential role in yes-associated protein nuclear translocation during the early phase of trypanosoma cruzi infection in heart endothelial cells. Int J Mol Sci. https://doi.org/10.3390/ijms21144912
Aya-Bonilla C et al (2013) High-resolution loss of heterozygosity screening implicates PTPRJ as a potential tumor suppressor gene that affects susceptibility to Non-Hodgkin’s lymphoma. Genes Chromosomes Cancer 52:467–479. https://doi.org/10.1002/gcc.22044
Baguma-Nibasheka M, Kablar B (2008) Pulmonary hypoplasia in the connective tissue growth factor (Ctgf) null mouse. DevDyn 237:485–493. https://doi.org/10.1002/dvdy.21433
Barclay AN, Van den Berg TK (2014) The interaction between signal regulatory protein alpha (SIRPalpha) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 32:25–50. https://doi.org/10.1146/annurev-immunol-032713-120142
Bender HR, Campbell GE, Aytoda P, Mathiesen AH, Duffy DM (2019) Thrombospondin 1 (THBS1) promotes follicular angiogenesis, luteinization, and ovulation in primates. Front Endocrinol (Lausanne) 10:727. https://doi.org/10.3389/fendo.2019.00727
Bentley SR et al (2020) Evidence of a recessively inherited CCN3 mutation as a rare cause of early-onset parkinsonism. Front Neurol 11:331. https://doi.org/10.3389/fneur.2020.00331
Binsker U, Kohler TP, Hammerschmidt S (2019) Contribution of human thrombospondin-1 to the pathogenesis of gram-positive bacteria. J Innate Immun 11:303–315. https://doi.org/10.1159/000496033
Bornstein P (1995) Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol 130:503–506. https://doi.org/10.1083/jcb.130.3.503
Bouleftour W et al (2016) The role of the SIBLING, Bone Sialoprotein in skeletal biology - Contribution of mouse experimental genetics. Matrix Biol 52–54:60–77. https://doi.org/10.1016/j.matbio.2015.12.011
Bradshaw AD (2009) The role of SPARC in extracellular matrix assembly. J Cell Commun Signal 3:239–246. https://doi.org/10.1007/s12079-009-0062-6
Bristow J, Carey W, Egging D, Schalkwijk J (2005) Tenascin-X, collagen, elastin, and the Ehlers–Danlos syndrome. Am J Med Genet C Semin Med Genet 139C:24–30. https://doi.org/10.1002/ajmg.c.30071
Bruce LJ et al (2002) Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex. Blood 100:1878–1885. https://doi.org/10.1182/blood-2002-03-0706
Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE, Mouse Genome Database G (2019) Mouse Genome Database (MGD) 2019. Nucleic Acids Res 47:D801–D806. https://doi.org/10.1093/nar/gky1056
Burashnikov E et al (2010) Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 7:1872–1882. https://doi.org/10.1016/j.hrthm.2010.08.026
Burke A, Creighton W, Tavora F, Li L, Fowler D (2009) Decreased frequency of the 3’UTR T>G single nucleotide polymorphism of thrombospondin-2 gene in sudden death due to plaque erosion. Cardiovasc Pathol. https://doi.org/10.1016/j.carpath.2008.12.013
Calabro NE, Kristofik NJ, Kyriakides TR (2014) Thrombospondin-2 and extracellular matrix assembly. Biochim Biophys Acta 1840:2396–2402. https://doi.org/10.1016/j.bbagen.2014.01.013
Calzada MJ, Roberts DD (2005) Novel integrin antagonists derived from thrombospondins. Curr Pharm Des 11:849–866
Canalis E, Smerdel-Ramoya A, Durant D, Economides AN, Beamer WG, Zanotti S (2010) Nephroblastoma overexpressed (Nov) inactivation sensitizes osteoblasts to bone morphogenetic protein-2, but Nov is dispensable for skeletal homeostasis. Endocrinology 151:221–233. https://doi.org/10.1210/en.2009-0574
Carlson CB, Liu Y, Keck JL, Mosher DF (2008) Influences of the N700S thrombospondin-1 polymorphism on protein structure and stability. J Biol Chem 283:20069–20076. https://doi.org/10.1074/jbc.m800223200
Chilongola J, Balthazary S, Mpina M, Mhando M, Mbugi E (2009) CD36 deficiency protects against malarial anaemia in children by reducing Plasmodium falciparum-infected red blood cell adherence to vascular endothelium. Trop Med Int Health 14:810–816. https://doi.org/10.1111/j.1365-3156.2009.02298.x
Coban-Akdemir Z et al (2018) Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles. Am J Hum Genet 103:171–187. https://doi.org/10.1016/j.ajhg.2018.06.009
Collins M, Rojnuckarin P, Zhu YH, Bornstein P (1998) A far upstream, cell type-specific enhancer of the mouse thrombospondin 3 gene is located within intron 6 of the adjacent metaxin gene. J Biol Chem 273:21816–21824. https://doi.org/10.1074/jbc.273.34.21816
Curtis BR, Aster RH (1996) Incidence of the Nak(a)-negative platelet phenotype in African Americans is similar to that of Asians. Transfusion 36:331–334. https://doi.org/10.1046/j.1537-2995.1996.36496226147.x
Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP (1997) CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 138:707–717. https://doi.org/10.1083/jcb.138.3.707
de La Dure-Molla M, Philippe Fournier B, Berdal A (2015) Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification. Eur J Hum Genet 23:445–451. https://doi.org/10.1038/ejhg.2014.159
DeGroot MS, Shi H, Eastman A, McKillop AN, Liu J (2019) The Caenorhabditis elegans SMOC-1 protein acts cell nonautonomously to promote bone morphogenetic protein signaling. Genetics 211:683–702. https://doi.org/10.1534/genetics.118.301805
Dhamija R, Graham JM Jr, Smaoui N, Thorland E, Kirmani S (2014) Novel de novo SPOCK1 mutation in a proband with developmental delay, microcephaly and agenesis of corpus callosum. Eur J Med Genet 57:181–184. https://doi.org/10.1016/j.ejmg.2014.02.009
Dufresne D, Hamdan FF, Rosenfeld JA, Torchia B, Rosenblatt B, Michaud JL, Srour M (2012) Homozygous deletion of Tenascin-R in a patient with intellectual disability. J Med Genet 49:451–454. https://doi.org/10.1136/jmedgenet-2012-100831
Duquette M, Nadler M, Okuhara D, Thompson J, Shuttleworth T, Lawler J (2014) Members of the thrombospondin gene family bind stromal interaction molecule 1 and regulate calcium channel activity. Matrix Biol 37:15–24. https://doi.org/10.1016/j.matbio.2014.05.004
Elola MT, Wolfenstein-Todel C, Troncoso MF, Vasta GR, Rabinovich GA (2007) Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival. Cell Mol Life Sci 64:1679–1700. https://doi.org/10.1007/s00018-007-7044-8
Eroglu C et al (2009) Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139:380–392. https://doi.org/10.1016/j.cell.2009.09.025
Farlow JL et al (2016) Whole-exome sequencing in familial parkinson disease. JAMA Neurol 73:68–75. https://doi.org/10.1001/jamaneurol.2015.3266
Feng JQ et al (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38:1310–1315. https://doi.org/10.1038/ng1905
Feske S (2010) CRAC channelopathies. Pflugers Arch 460:417–435. https://doi.org/10.1007/s00424-009-0777-5
Frolova EG et al (2010) Thrombospondin-4 regulates vascular inflammation and atherogenesis. Circ Res 107:1313–1325. https://doi.org/10.1161/CIRCRESAHA.110.232371
Gilmour DT et al (1998) Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens. EMBO J 17:1860–1870. https://doi.org/10.1093/emboj/17.7.1860
Gonias SL, Wu L, Salicioni AM (2004) Low density lipoprotein receptor-related protein: regulation of the plasma membrane proteome. Thromb Haemost 91:1056–1064. https://doi.org/10.1160/TH04-01-0023
Greenaway J, Lawler J, Moorehead R, Bornstein P, Lamarre J, Petrik J (2007) Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1). J Cell Physiol 210:807–818. https://doi.org/10.1002/jcp.20904
Hankenson KD, Hormuzdi SG, Meganck JA, Bornstein P (2005a) Mice with a disruption of the thrombospondin 3 gene differ in geometric and biomechanical properties of bone and have accelerated development of the femoral head. Mol Cell Biol 25:5599–5606. https://doi.org/10.1128/mcb.25.13.5599-5606.2005
Hankenson KD et al (2005b) Increased osteoblastogenesis and decreased bone resorption protect against ovariectomy-induced bone loss in thrombospondin-2-null mice. Matrix Biol 24:362–370. https://doi.org/10.1016/j.matbio.2005.05.008
Hatherley D, Graham SC, Turner J, Harlos K, Stuart DI, Barclay AN (2008) Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47. Mol Cell 31:266–277. https://doi.org/10.1016/j.molcel.2008.05.026
Hawi Z et al (2018) A case-control genome-wide association study of ADHD discovers a novel association with the tenascin R (TNR) gene. Transl Psychiatry 8:284. https://doi.org/10.1038/s41398-018-0329-x
Herz J, Clouthier DE, Hammer RE (1992) LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell 71:411–421. https://doi.org/10.1016/0092-8674(92)90511-a
Hirano K, Kuwasako T, Nakagawa-Toyama Y, Janabi M, Yamashita S, Matsuzawa Y (2003) Pathophysiology of human genetic CD36 deficiency. Trends Cardiovasc Med 13:136–141. https://doi.org/10.1016/s1050-1738(03)00026-4
Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119:3901–3903. https://doi.org/10.1242/jcs.03098
Hurvitz JR et al (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23:94–98. https://doi.org/10.1038/12699
Isenberg JS et al (2007) Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Blood 109:1945–1952. https://doi.org/10.1182/blood-2006-08-041368
Isenberg JS et al (2008a) Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. Am J Pathol 173:1100–1112. https://doi.org/10.2353/ajpath.2008.080237
Isenberg JS, Romeo MJ, Maxhimer JB, Smedley J, Frazier WA, Roberts DD (2008b) Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease. Ann Surg 247:860–868. https://doi.org/10.1097/SLA.0b013e31816c4006
Ivkovic S et al (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130:2779–2791. https://doi.org/10.1242/dev.00505
Jones FS, Jones PL (2000) The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling. Dev Dyn 218:235–259
Karczewski KJ et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7
Kaur S et al (2011) Heparan sulfate modification of the transmembrane receptor CD47 is necessary for inhibition of T cell receptor signaling by thrombospondin-1. J Biol Chem 286:14991–15002. https://doi.org/10.1074/jbc.M110.179663
Kawaki H et al (2008) Functional requirement of CCN2 for intramembranous bone formation in embryonic mice. Biochem Biophys Res Commun 366:450–456. https://doi.org/10.1016/j.bbrc.2007.11.155
Kim KH, Won JH, Cheng N, Lau LF (2018) The matricellular protein CCN1 in tissue injury repair. J Cell Commun Signal 12:273–279. https://doi.org/10.1007/s12079-018-0450-x
Knight MN, Hankenson KD (2014) R-spondins: novel matricellular regulators of the skeleton. Matrix Biol 37:157–161. https://doi.org/10.1016/j.matbio.2014.06.003
Kontarakis Z, Stainier DYR (2020) Genetics in light of transcriptional adaptation. Trends Genet 36:926–935. https://doi.org/10.1016/j.tig.2020.08.008
Kutz WE, Gong Y, Warman ML (2005) WISP3, the gene responsible for the human skeletal disease progressive pseudorheumatoid dysplasia, is not essential for skeletal function in mice. Mol Cell Biol 25:414–421. https://doi.org/10.1128/mcb.25.1.414-421.2005
Lacruz RS, Feske S (2015) Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci 1356:45–79. https://doi.org/10.1111/nyas.12938
Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO (1998) Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 101:982–992. https://doi.org/10.1172/JCI1684
Leask A (2020) Conjunction junction, what’s the function? CCN proteins as targets in fibrosis and cancers. Am J Physiol Cell Physiol 318:C1046–C1054. https://doi.org/10.1152/ajpcell.00028.2020
Lek M et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057
Liang T, Zhang H, Xu Q, Wang S, Qin C, Lu Y (2019) Mutant dentin sialophosphoprotein causes dentinogenesis imperfecta. J Dent Res 98:912–919. https://doi.org/10.1177/0022034519854029
Lindberg FP, Bullard DC, Caver TE, Gresham HD, Beaudet AL, Brown EJ (1996) Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274:795–798. https://doi.org/10.1126/science.274.5288.795
Liu J et al (2020) Distribution of CD36 deficiency in different Chinese ethnic groups. Hum Immunol 81:366–371. https://doi.org/10.1016/j.humimm.2020.05.004
Lorenz-Depiereux B et al (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248–1250. https://doi.org/10.1038/ng1868
Marconi C et al (2019) Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia. Blood 133:1346–1357. https://doi.org/10.1182/blood-2018-07-859496
Martin-Manso G, Navarathna DH, Galli S, Soto-Pantoja DR, Kuznetsova SA, Tsokos M, Roberts DD (2012a) Endogenous thrombospondin-1 regulates leukocyte recruitment and activation and accelerates death from systemic candidiasis. PLoS ONE 7:e48775. https://doi.org/10.1371/journal.pone.0048775
McMaken S et al (2011) Thrombospondin-1 contributes to mortality in murine sepsis through effects on innate immunity. PLoS ONE 6:e19654. https://doi.org/10.1371/journal.pone.0019654
Mendoza-Londono R et al (2015) Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet 96:979–985. https://doi.org/10.1016/j.ajhg.2015.04.021
Midwood KS, Orend G (2009) The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal. https://doi.org/10.1007/s12079-009-0075-1
Miyaoka K, Kuwasako T, Hirano K, Nozaki S, Yamashita S, Matsuzawa Y (2001) CD36 deficiency associated with insulin resistance. Lancet 357:686–687. https://doi.org/10.1016/s0140-6736(00)04138-6
Mo FE, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969. https://doi.org/10.1161/01.RES.0000248426.35019.89
Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF (2002) CYR61 (CCN1) is essential for placental development and vascular integrity. Mol Cell Biol 22:8709–8720. https://doi.org/10.1128/mcb.22.24.8709-8720.2002
Murphy-Ullrich JE, Sage EH (2014) Revisiting the matricellular concept. Matrix Biol 37:1–14. https://doi.org/10.1016/j.matbio.2014.07.005
Nagaraju GP, Dontula R, El-Rayes BF, Lakka SS (2014) Molecular mechanisms underlying the divergent roles of SPARC in human carcinogenesis. Carcinogenesis 35:967–973. https://doi.org/10.1093/carcin/bgu072
Nakamura T (2018) Roles of short fibulins, a family of matricellular proteins, in lung matrix assembly and disease. Matrix Biol 73:21–33. https://doi.org/10.1016/j.matbio.2018.02.003
Okada I et al (2011) SMOC1 is essential for ocular and limb development in humans and mice. Am J Hum Genet 88:30–41. https://doi.org/10.1016/j.ajhg.2010.11.012
Pallero MA, Elzie CA, Chen J, Mosher DF, Murphy-Ullrich JE (2008) Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. Faseb J 22:3968–3979. https://doi.org/10.1096/fj.07-104802
Posey KL, Coustry F, Hecht JT (2018) Cartilage oligomeric matrix protein: COMPopathies and beyond. Matrix Biol 71–72:161–173. https://doi.org/10.1016/j.matbio.2018.02.023
Posey KL, Hankenson K, Veerisetty AC, Bornstein P, Lawler J, Hecht JT (2008) Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin-1, thrombospondin-3, thrombospondin-5, and type IX collagen. Am J Pathol 172:1664–1674. https://doi.org/10.2353/ajpath.2008.071094
Qu Y et al (2018) Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysis. JCI Insight. https://doi.org/10.1172/jci.insight.96914
Rainger J et al (2011) Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice. PLoS Genet 7:e1002114. https://doi.org/10.1371/journal.pgen.1002114
Resovi A, Pinessi D, Chiorino G, Taraboletti G (2014) Current understanding of the thrombospondin-1 interactome. Matrix Biol 37:83–91. https://doi.org/10.1016/j.matbio.2014.01.012
Roberts DD, Miller TW, Rogers NM, Yao M, Isenberg JS (2012) The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress. Matrix Biol 31:162–169. https://doi.org/10.1016/j.matbio.2012.01.005
Roll S, Seul J, Paulsson M, Hartmann U (2006) Testican-1 is dispensable for mouse development. Matrix Biol 25:373–381. https://doi.org/10.1016/j.matbio.2006.05.004
Ruivenkamp CA et al (2002) Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 31:295–300. https://doi.org/10.1038/ng903
Song YL, Wang CN, Fan MW, Su B, Bian Z (2008) Dentin phosphoprotein frameshift mutations in hereditary dentin disorders and their variation patterns in normal human population. J Med Genet 45:457–464. https://doi.org/10.1136/jmg.2007.056911
Soto-Pantoja DR, Kaur S, Roberts DD (2015) CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol 50:212–230. https://doi.org/10.3109/10409238.2015.1014024
Staines KA, MacRae VE, Farquharson C (2012) The importance of the SIBLING family of proteins on skeletal mineralisation and bone remodelling. J Endocrinol 214:241–255. https://doi.org/10.1530/JOE-12-0143
Stenina-Adognravi O, Plow EF (2019) Thrombospondin-4 in tissue remodeling. Matrix Biol 75–76:300–313. https://doi.org/10.1016/j.matbio.2017.11.006
Stenina OI, Topol EJ, Plow EF (2007) Thrombospondins, their polymorphisms, and cardiovascular disease. Arterioscler Thromb Vasc Biol 27:1886–1894
Stenina OI, Ustinov V, Krukovets I, Marinic T, Topol EJ, Plow EF (2005) Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites. Faseb J 19:1893–1895. https://doi.org/10.1096/fj.05-3712fje
Sun LR, Li SY, Guo QS, Zhou W, Zhang HM (2020) SPOCK1 involvement in epithelial-to-mesenchymal transition: a new target in cancer therapy? Cancer Manag Res 12:3561–3569. https://doi.org/10.2147/CMAR.S249754
Svensson L, Aszodi A, Heinegard D, Hunziker EB, Reinholt FP, Fassler R, Oldberg A (2002) Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol 22:4366–4371. https://doi.org/10.1128/mcb.22.12.4366-4371.2002
Takahashi K et al (2012) Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc Natl Acad Sci U S A 109:1985–1990. https://doi.org/10.1073/pnas.1106171109
Taylor CP, Harris EW (2020) Analgesia with gabapentin and pregabalin may involve N-methyl-d-aspartate receptors neurexins, and thrombospondins. J Pharmacol Exp Ther 374:161–174. https://doi.org/10.1124/jpet.120.266056
Templin C et al (2011) Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J 32:1077–1088. https://doi.org/10.1093/eurheartj/ehr076
Tolsma SS, Volpert OV, Good DJ, Frazier WA, Polverini PJ, Bouck N (1993) Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J Cell Biol 122:497–511. https://doi.org/10.1083/jcb.122.2.497
Topol EJ et al (2001) Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 104:2641–2644. https://doi.org/10.1161/hc4701.100910
Trapasso F et al (2006) Genetic ablation of Ptprj, a mouse cancer susceptibility gene, results in normal growth and development and does not predispose to spontaneous tumorigenesis DNA. Cell Biol 25:376–382. https://doi.org/10.1089/dna.2006.25.376
Varga-Szabo D et al (2008) The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 205:1583–1591. https://doi.org/10.1084/jem.20080302
Vergult S et al (2015) Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability. Eur J Hum Genet 23:628–632. https://doi.org/10.1038/ejhg.2014.141
Wagner M et al (2020) Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus. Genet Med 22:1061–1068. https://doi.org/10.1038/s41436-020-0768-7
Weber P et al (1999) Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J Neurosci 19:4245–4262. https://doi.org/10.1523/jneurosci.19-11-04245.1999
Yuasa-Kawase M et al (2012) Patients with CD36 deficiency are associated with enhanced atherosclerotic cardiovascular diseases. J Atheroscler Thromb 19:263–275. https://doi.org/10.5551/jat.10603
Zhang X et al (2001) DSPP mutation in dentinogenesis imperfecta Shields type II. Nat Genet 27:151–152. https://doi.org/10.1038/84765
Zhao Y et al (2015) Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection. Mucosal Immunol 8:896–905. https://doi.org/10.1038/mi.2014.120
Funding
This work was supported by the Intramural Research Program of the NIH/NCI (ZIA SC009172).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kaur, S., Roberts, D.D. Differential intolerance to loss of function and missense mutations in genes that encode human matricellular proteins. J. Cell Commun. Signal. 15, 93–105 (2021). https://doi.org/10.1007/s12079-020-00598-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12079-020-00598-9