Professor Michael Briggs
Professor of Skeletal Genetics
- Email: email@example.com
- Telephone: +44 (0) 191 241 8820
- Fax: +44 (0) 191 241 8666
- Personal Website: http://mikebriggs1910.wordpress.com
- Address: Institute of Genetic Medicine
International Centre for Life
Newcastle upon Tyne
- From October 1989 to September 1992, I was a PhD Student in the MRC Clinical Research Centre at Harrow investigating the molecular defects of type I collagen in osteogenesis imperfecta.
- From October 1992 to October 1993, I was a Research Fellow in the Division of Medical Genetics at UCLA/Cedars Sinai Medical Centre. This was a 3-year Training Fellowship in the UCLA Intercampus Medical Genetics Training Program and the project involved the genetic mapping of PSACH and MED mutations in large families with these diseases.
- In July 1995, I was awarded a Research Fellowship from the Arthritis Research Campaign and moved to the University of Manchester.
- In January 2004, I started a 5-year Wellcome Trust Senior Research Fellowship (SRF) and during this time we studied the disease mechanisms of matrilin-3 and COMP mutations in vitro and generated of the first mouse models of PSACH-MED. In April 2008, I was awarded a 5-year renewal of my SRF.
- In June 2012 I moved to Newcastle as Professor of Skeletal Genetics.
During endochondral bone growth, chondrocytes in the growth plate undergo a highly coordinated and tightly controlled process of proliferation, hypertrophy and finally apoptosis at the vascular invasion front. Chondrocyte proliferation and hypertrophy is vital for correct long bone growth, whilst apoptosis of terminal hypertrophic chondrocytes plays a critical role in the transition from chondrogenesis to osteogenesis. Disruptions to these processes lead to growth plate dysplasia and result in a heterogeneous group of genetic diseases known as skeletal dysplasias that are characterised predominantly by short-limb dwarfism.
The scientific story
At each stage of maturation in the growth plate, chondrocytes synthesise and secrete specific structural proteins that are incorporated into the extracellular matrix (ECM). For example, cartilage oligomeric matrix protein (COMP) and matrilin-3 are expressed to the greatest extent by resting and proliferative chondrocytes, whilst type X collagen is expressed exclusively by hypertrophic chondrocytes. The expression of mutant forms of these cartilage structural proteins causes endoplasmic reticulum (ER) stress and induces an unfolded protein response (UPR). Briefly, the UPR is a sophisticated quality control system that aims to reduce ER stress through the activation of a number of different pathways that are mediated by three receptors, IRE1, ATF6 and PERK, and involving other downstream factors such as Xbp-1 and eIF2a. However, if ER homeostasis is not achieved then prolonged ER stress can eventually result in CHOP-mediated apoptosis.
We have shown using genetically engineered mouse models that the induction of ER stress and the UPR, through the expression of mutant COMP, matrilin-3 and type X collagen, can directly affect chondrocyte phenotype and cause growth plate dysplasia leading to short-limb dwarfism. Interestingly, although these mouse models all exhibit ER stress and an UPR, the different pathways that are activated appear to be gene and/or mutation specific. It is not clear in these archetypal examples of prolonged ER stress, whether the UPR is chondrocyte protective or a significant cause of distress. Answering this fundamental question will not only explain the initiation and progression of skeletal dysplasias, but will provide essential insight into disease mechanisms in many different diseases in which ER stress and UPR has been implicated.
- Hartley CL, Edwards S, Mullan L, Bell PA, Fresquet M, Boot-Handford RP, Briggs MD. Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases. Human Molecular Genetics 2013, 22, 5262-5275.
- Suleman F, Gualeni B, Gregson HJ, Leighton MP, Piróg KA, Edwards S, Holden P, Boot-Handford RP, Briggs MD. A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Human Mutation 2012, 33(1), 218-231.
- Bell PA, Piróg KA, Fresquet M, Thornton DJ, Boot-Handford RP, Briggs MD. Loss of matrilin 1 does not exacerbate the skeletal phenotype in a mouse model of multiple epiphyseal dysplasia caused by a Matn3 V194D mutation. Arthritis & Rheumatism 2012, 64(5), 1529-1539.
- Jackson G, Mittaz-Crettol L, Taylor J, Mortier G, Spranger J, Zabel B, Le Merrer M, Cormier-Daire V, Hall C, Offiah A, Wright M, Savarirayan R, Nishimura G, Ramsden S, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs M. Pseudoachondroplasia and multiple epiphyseal dysplasia: A 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Human Mutation 2012, 33(1), 144-157.
- Boyden ED, Campos-Xavier AB, Kalamajski S, Cameron TL, Suarez P, Tanackovic G, Andria G, Ballhausen D, Briggs MD, Hartley C, Cohn DH, Davidson HR, Hall C, Ikegawa S, Jouk PS, Konig R, Megarbane A, Nishimura G, Lachman RS, Mortier G, Rimoin DL, Rogers RC, Rossi M, Sawada H, Scott R, Unger S, Valadares ER, Bateman JF, Warman ML, Superti-Furga A, Bonafe L. Recurrent Dominant Mutations Affecting Two Adjacent Residues in the Motor Domain of the Monomeric Kinesin KIF22 Result in Skeletal Dysplasia and Joint Laxity (vol 89, pg 769, 2011). American Journal of Human Genetics 2012, 90(1), 170.
- Boyden ED, Campos-Xavier AB, Kalamajski S, Cameron TL, Suarez P, Tanackovich G, Andria G, Ballhausen D, Briggs MD, Hartley C, Cohn DH, Davidson HR, Hal C, Ikegawa S, Jouk PS, Konig R, Megarbane A, Nishimura G, Lachman RS, Mortier G, Rimoin DL, Rogers RC, Rossi M, Sawada H, Scott R, Unger S, Valadares ER, Bateman JF, Warman ML, Superti-Furga A, Bonafe L. Recurrent Dominant Mutations Affecting Two Adjacent Residues in the Motor Domain of the Monomeric Kinesin KIF22 Result in Skeletal Dysplasia and Joint Laxity. American Journal of Human Genetics 2011, 89(6), 767-772.
- Piróg KA, Jaka O, Katakura Y, Meadows RS, Kadler KE, Boot-Handford RP, Briggs MD. A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia. Human Molecular Genetics 2010, 19(1), 52-64.
- Nundlall S, Rajpar MH, Bell PA, Clowes C, Zeeff LAH, Gardner B, Thornton DJ, Boot-Handford RP, Briggs MD. An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia. Cell Stress and Chaperones 2010, 15(6), 835-849.
- Pirog KA, Briggs MD. Skeletal Dysplasias Associated with Mild Myopathy-A Clinical and Molecular Review. Journal of Biomedicine and Biotechnology 2010, Article no. 686457.
- Fresquet M, Jowitt TA, Stephen LA, Ylostalo J, Briggs MD. Structural ad functional investigations of Matrillin-1 a-domains reveal insights into their role in cartilage ECM assembly. Journal of Biological Chemistry 2010, 285(44), 34048-34061.
- Boot-Handford RP, Briggs M. The unfolded protein response and its relevance to connective tissue diseases. Cell and Tissue Research 2010, 339(1), 197-211.
- Jackson GD, Marcus-Soekarman D, Stolte-Dijkstra I, Verrips A, Taylor JA, Briggs MD. Type IX Collagen Gene Mutations can result in Multiple Epiphyseal Dysplasia that is associated with Osteochondritis Dissecans and a Mild Myopathy. American Journal of Medical Genetics Part A 2010, 152A(4), 863-869.
- Tompson S, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, Nelson SF, Briggs MD, Cohn DH, Krakow D. A Recessive Skeletal Dysplasia, SEMD Aggrecan Type, Results from a Missense Mutation Affecting the C-Type Lectin Domain of Aggrecan. American Journal of Human Genetics 2009, 84(1), 72-79.
- Rajpar MH, McDermott B, Kung L, Eardley R, Knowles L, Heeran M, Thornton DJ, Wilson R, Bateman JF, Poulsom R, Arvan P, Kadler KE, Briggs MD, Boot-Handford RP. Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genetics 2009, 5(10), e1000691.
- Fresquet M, Jackson GC, Loughlin J, Briggs MD. Novel mutations in exon 2 of MATN3 affect residues within the alpha-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3. Human Mutation 2008, 29(2), 330.
- Plumb DA, Dhir V, Mironov A, Ferrara L, Poulsom R, Kadler KE, Thornton DJ, Briggs MD, Boot-Handford RP. Collagen XXVII is developmentally regulated and forms thin fibrillar structures distinct from those of classical vertebrate fibrillar collagens. Journal of Biological Chemistry 2007, 282(17), 12791-12795.
- Leighton MP, Nundlall S, Starborg T, Meadows RS, Suleman F, Knowles L, Wagener R, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation. Human Molecular Genetics 2007, 16(14), 1728-1741.
- Zankl A, Jackson GC, Crettol LM, Taylor J, Elles R, Mortier GR, Spranger J, Zabel B, Unger S, Le Merrer M, Cormier-Daire V, Hall CM, Wright MJ, Bonafe L, Superti-Furga A, Briggs MD. Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia. European Journal of Human Genetics 2007, 15(2), 150-154.
- Pirog-Garcia KA, Meadows RS, Knowles L, Heinegard D, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Human Molecular Genetics 2007, 16(17), 2072-2088.
- Fresquet M, Jowitt TA, Ylostalo J, Coffey P, Meadows RS, Ala-Kokko L, Thornton DJ, Briggs MD. Structural and functional characterization of recombinant matrilin-3 A-domain and implications for human genetic bone diseases. Journal of Biological Chemistry 2007, 282(48), 34634-34643.
- Saeed S, Briggs M, Lobo C, Al-Zoubi F, Ramsden R, Read A. The genetics of otosclerosis: pedigree studies and linkage analysis. Otosclerosis and Stapes Surgery 2007, 65, 75-85.
- Spranger JW, Zabel B, Kennedy J, Jackson G, Briggs M. A disorder resembling pseudoachondroplasia but without COMP mutation. American Journal of Medical Genetics Part A 2005, 132A(1), 20-24.
- Kennedy J, Jackson G, Ramsden S, Taylor J, Newman W, Wright MJ, Donnai D, Elles R, Briggs MD. COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. European Journal of Human Genetics 2005, 13(5), 547-555.
- Cotterill SL, Jackson GC, Leighton MR, Wagener R, Makitie O, Cole WG, Briggs MD. Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. Human Mutation 2005, 26(6), 557-565.
- Jakkula E, Makitie O, Czarny-Ratajczak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L. Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. European Journal of Human Genetics 2005, 13(10), 1166-1166.
- Kennedy J, Jackson GC, Barker FS, Nundlall S, Bella J, Wright MJ, Mortier GR, Neas K, Thompson E, Elles R, Briggs MD. Novel and recurrent mutations in the C-terminal domain of COMP cluster in two distinct regions and result in a spectrum of phenotypes within the pseudoachondroplasia – multiple epiphyseal dysplasia disease group. Human Mutation 2005, 25(6), 593-594.
- Makitie O, Mortier GR, Czarny-Ratajczak M, Wright MJ, Suri M, Rogala P, Freund M, Jackson GC, Jakkula E, Ala-Kokko L, Briggs MD, Cole WG. Clinical and Radiographic Findings in Multiple Epiphyseal Dysplasia Caused by MATN3 Mutations: Description of 12 Patients. American Journal of Medical Genetics Part A 2004, 125(3), 278-284.
- Jackson GC, Barker FS, Jakkula E, Czarny-Ratajczak M, Makitie O, Cole WG, Wright MJ, Smithson SF, Suri M, Rogala P, Mortier GR, Baldock C, Wallace A, Elles R, Ala-Kokko L, Briggs MD. Missense mutations in the β strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. Journal of Medical Genetics 2004, 41(1), 52-59.
- Chapman KL, Briggs MD, Mortier GR. Review: Clinical variability and genetic heterogeneity in multiple epiphyseal dysplasia. Pediatric Pathology and Molecular Medicine 2003, 22(1), 53-75.
- Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: Mutation review, molecular interactions, and genotype to phenotype correlations. Human Molecular Genetics 2002, 19(5), 465-478.
- Holden P, Meadows RS, Chapman KL, Grant ME, Kadler KE, Briggs MD. Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family. Journal of Biological Chemistry 2001, 276(8), 6046-6055.
- Mortier GR, Chapman K, Leroy JL, Briggs MD. Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes. European Journal of Human Genetics 2001, 9(8), 606-612.
- Unger SL, Briggs MD, Holden P, Zabel B, Ala-Kokko L, Paassilta P, Lohiniva J, Rimoin DL, Lachman RS, Cohn DH. Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype. In: 4th International Skeletal Dysplasia Meeting. 2001, Baden Baden, Germany: Springer.
- Chapman KL, Mortier GR, Chapman K, Loughlin J, Grant ME, Briggs MD. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nature Genetics 2001, 28(4), 393-396.
- Spayde EC, Joshi AP, Wilcox WR, Briggs M, Cohn DH, Olsen BR. Exon skipping mutation in the COL9A2 gene in a family with multiple epiphyseal dysplasia. Matrix Biology 2000, 19(2), 121-128.
- Reardon AJ, LeGoff M, Briggs MD, McLeod D, Sheehan JK, Thornton DJ, Bishop PN. Identification in vitreous and molecular cloning of opticin, a novel member of the family of leucine-rich repeat proteins of the extracellular matrix. Journal of Biological Chemistry 2000, 275(3), 2123-2129.
- Newman B, Donnai D, Briggs MD. Molecular diagnosis is important to confirm suspected pseudoachondroplasia. Journal of Medical Genetics 2000, 37(1), 64-65.
- Briggs MD. Screening for mutations in cartilage ECM genes. In: Streuli, C., Grant, M, ed. Extracellular Matrix Protocols. London: Humana Press, 2000, pp.133-145.
- Holden P, Canty EG, Mortier GR, Zabel B, Spranger J, Carr A, Grant ME, Loughlin JA, Briggs MD. Identification of novel pro-alpha 2(IX) collagen gene mutations in two families with distinctive olgo-epiphyseal forms of multiple epiphyseal dysplasia. American Journal of Human Genetics 1999, 65(1), 31-38.
- Delot E, King LM, Briggs MD, Wilcox WR, Cohn DH. Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene. Human Molecular Genetics 1999, 8(1), 123-128.
- Briggs MD, Mortier GR, Cole WG, King LM, Golik SS, Bonaventure J, Nuytinck L, DePaepe A, Leroy JG, Biesecker L, Lipson M, Wilcox WR, Lachman RS, Rimoin DL, Knowlton RG, Cohn DH. Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia multiple epiphyseal dysplasia disease spectrum. American Journal of Human Genetics 1998, 62(2), 311-319.
- Loughlin J, Irven C, Mustafa Z, Briggs MD, Carr A, Lynch SA, Knowlton RG, Cohn DH, Sykes B. Identification of five novel mutations in cartilage oligomeric matrix protein gene in pseudoachrondroplasia and multiple epiphyseal dysplasia. Human Mutation 1998, (s1), S10-S17.
- Ballo R, Briggs MD, Cohn DH, Knowlton RG, Beighton PH, Ramesar RS. Multiple epiphyseal dysplasia, ribbing type: A novel point mutation in the COMP gene in a South African family. American Journal of Medical Genetics 1997, 68(4), 396-400.
- Cohn DH, Briggs MD, King LM, Rimoin DL, Wilcox WR, Lachman RS, Knowlton RG. Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal. In: Molecular and Developmental Biology of Cartilage. 1996, Bethesda, Maryland, USA: New York Academy of Sciences.
- Knowlton RG, Cekleniak JA, Cohn DH, Briggs MD, Hoffman SMG, Brandriff BF, Olsen AS. High-resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1-p12. Genomics 1995, 28(3), 513-519.
- Briggs MD, Hoffman SMG, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES, Cekleniak JA, Knowlton RG, Cohn DH. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nature Genetics 1995, 10(3), 330-336.
- Rimoin DL, Rasmussen IM, Briggs MD, Roughley PJ, Gruber HE, Warman ML, Olsen BR, Hsia YE, Yuen J, Reinker K, Garber AP, Grover J, Lachman RS, Cohn DH. A large family with features of pseudoachondroplasia and multiple epiphyseal dysplasia - exclusion of 7 candidate gene loci that encode proteins of the cartilage extracellular-matrix. Human Genetics 1994, 93(3), 236-242.
- Briggs MD, Choi HC, Warman ML, Loughlin JA, Wordsworth P, Sykes BC, Irven CMM, Smith M, Wynnedavies R, Lipson MH, Biesecker LG, Garber AP, Lachman R, Olsen BR, Rimoin DL, Cohn DH. Genetic-mapping of a locus for multiple epiphyseal dysplasia (edm2) to a region of chromosome-i containing a type ix collagen gene. American Journal Of Human Genetics 1994, 55(4), 678-684.
- Briggs MD, Rasmussen IM, Weber JL, Yuen J, Reinker K, Garber AP, Rimoin DL, Cohn DH. Genetic-linkage of mild pseudoachondroplasia (psach) to markers in the pericentromeric region of chromosome-19. Genomics 1993, 18(3), 656-660.
- Hecht JT, Francomano CA, Briggs MD, Deere M, Conner B, Horton WA, Warman M, Cohn DH, Blanton SH. Linkage of typical pseudoachondroplasia to chromosome-19. Genomics 1993, 18(3), 661-666.
- Bell PA, Wagener R, Zaucke F, Koch M, Selley J, Warwood S, Knight D, Boot-Handford RP, Thornton DJ, Briggs MD. Analysis of the cartilage proteome from three different mouse models of genetic skeletal diseases reveals common and discrete disease signatures. Biology Open 2013, 2(8), 802-811.
- Boot-Handford RP, Kung LH, Mullan L, Mularczyk EJ, Briggs MD. ER stress: a new regulator of chondrocyte biology and cartilage health. In: 2016 OARSI World Congress on Osteoarthritis: Promoting Clinical and Basic Research in Osteoarthritis. 2016, Amsterdam, The Netherlands: Elsevier.
- Gibson BG, Briggs MD. The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases. Orphanet Journal of Rare Diseases 2016, 11, 86.
- Cameron TL, Gresshoff IL, Bell KM, Piróg KA, Sampurno L, Hartley CL, Sanford EM, Wilson R, Ermann J, Boot-Handford RP, Glimcher LH, Briggs MD, Bateman JF. Cartilage-Specific Ablation of XBP1 Signaling in Mouse Results in a Chondrodysplasia Characterized by Reduced Chondrocyte Proliferation and Delayed Cartilage Maturation and Mineralization. Osteoarthritis and Cartilage 2015.
- Kung LHW, Rajpar MH, Preziosi R, Briggs MD, Boot-Handford RP. Increased Classical Endoplasmic Reticulum Stress Is Sufficient to Reduce Chondrocyte Proliferation Rate in the Growth Plate and Decrease Bone Growth. PLoS ONE 2015, 10(2), e0117016.
- Briggs MD, Bell PA, Wright MJ, Pirog KA. New therapeutic targets in rare genetic skeletal diseases. Expert Opinion on Orphan Drugs 2015, 3(10), 1137-1154.
- Briggs MD, Bell PA, Pirog KA. The utility of mouse models to provide information regarding the pathomolecular mechanisms in human genetic skeletal diseases: The emerging role of endoplasmic reticulum stress (Review). International Journal of Molecular Medicine 2015, 1483-1492.
- Piróg KA, Irman A, Young S, Halai P, Bell PA, Boot-Handford RP, Briggs MD. Abnormal Chondrocyte Apoptosis in the Cartilage Growth Plate is Influenced by Genetic Background and Deletion of CHOP in a Targeted Mouse Model of Pseudoachondroplasia. PLoS One 2014, 9(2), e85145.
- Briggs MD, Brock J, Ramsden SC, Bell PA. Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias. European Journal of Human Genetics 2014, 22(11), 1278-1282.
- Gualeni B, Rajpar MH, Kellogg A, Bell PA, Arvan P, Boot-Handford RP, Briggs MD. A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. Disease Models & Mechanisms 2013, 6(6), 1414-1425.
- Kung LHW, Mullan L, Briggs MD, Boot-Handford RP. Chondrocyte ER stress as a pathogenic factor in osteoarthritis. In: British Society for Matrix Biology Autumn 2013 Meeting. 2013, Cardiff: Wiley-Blackwell.
- Piróg KA, Katakura Y, Mironov A, Briggs MD. Mild myopathy is associated with COMP but not MATN3 mutations in mouse models of genetic skeletal diseases. PLoS One 2013, 8(11), e82412.
- Pirog KA, Meadows RS, Boot-Handford RP, Briggs MD. Mutant chondrocytes are characterised by altered cell shape and changes to the organisation of primary cilia in a genetic mouse model of mild pseudoachondroplasia. In: British Society for Matrix Biology Autumn 2013 Meeting. 2013, Cardiff: Wiley-Blackwell.