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5. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype

Author

De Vos, Ivo J.H.M., Tao, Evelyn Yaqiong, Ong, Sheena Li Ming, Goggi, Julian L., Scerri, Thomas, Wilson, Gabrielle R., Low, Chernis Guai Mun, Wong, Arnette Shi Wei, Grussu, Dominic, Stegmann, Alexander P.A., Van Geel, Michel, Janssen, Renske, Amor, David J., Bahlo, Melanie, Dunn, Norris R., Carney, Thomas J., Lockhart, Paul J., Coull, Barry J., Van Steensel, Maurice A.M., De Vos, Ivo J.H.M., Tao, Evelyn Yaqiong, Ong, Sheena Li Ming, Goggi, Julian L., Scerri, Thomas, Wilson, Gabrielle R., Low, Chernis Guai Mun, Wong, Arnette Shi Wei, Grussu, Dominic, Stegmann, Alexander P.A., Van Geel, Michel, Janssen, Renske, Amor, David J., Bahlo, Melanie, Dunn, Norris R., Carney, Thomas J., Lockhart, Paul J., Coull, Barry J., and Van Steensel, Maurice A.M.

Abstract

Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation in MMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murine MMP14 mutations, does not affect MMP14's transport to the cell membrane. Instead, it partially impairs MMP14's proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14's catalytic activity is the prime determinant of disease severity. Given the limitations of our in vitro assays in addressing the consequences of MMP14 dysfunction, we generated a novel mmp14a/b knockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.

Published
2018

6. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype

Author

de Vos, Ivo J H M, primary, Tao, Evelyn Yaqiong, additional, Ong, Sheena Li Ming, additional, Goggi, Julian L, additional, Scerri, Thomas, additional, Wilson, Gabrielle R, additional, Low, Chernis Guai Mun, additional, Wong, Arnette Shi Wei, additional, Grussu, Dominic, additional, Stegmann, Alexander P A, additional, van Geel, Michel, additional, Janssen, Renske, additional, Amor, David J, additional, Bahlo, Melanie, additional, Dunn, Norris R, additional, Carney, Thomas J, additional, Lockhart, Paul J, additional, Coull, Barry J, additional, and van Steensel, Maurice A M, additional

Published
2018
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8. 374. Developing Bone Marrow Transplant and Lentiviral Vectors to Treat Friedreich Ataxia

Author

Ong, Sze Hwee, primary, Zhang, Dong C., additional, Sim, Chou H., additional, Burton, Matthew, additional, Phelan, Dean, additional, Stephenson, Sarah E.M., additional, Wilson, Gabrielle R., additional, Newgreen, Donald F., additional, Hannan, Anthony J., additional, Lockhart, Paul J., additional, Delatycki, Martin B., additional, and Evans-Galea, Marguerite V., additional

Published
2016
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9. ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy

Author

Phelan, Dean G., primary, Anderson, David J., additional, Howden, Sara E., additional, Wong, Raymond C.B., additional, Hickey, Peter F., additional, Pope, Kate, additional, Wilson, Gabrielle R., additional, Pébay, Alice, additional, Davis, Andrew M., additional, Petrou, Steven, additional, Elefanty, Andrew G., additional, Stanley, Edouard G., additional, James, Paul A., additional, Macciocca, Ivan, additional, Bahlo, Melanie, additional, Cheung, Michael M., additional, Amor, David J., additional, Elliott, David A., additional, and Lockhart, Paul J., additional

Published
2016
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12. Mutations in RAB39B Cause X-Linked Intellectual Disability and Early-Onset Parkinson Disease with α-Synuclein Pathology

Author

Wilson, Gabrielle R., primary, Sim, Joe C.H., additional, McLean, Catriona, additional, Giannandrea, Maila, additional, Galea, Charles A., additional, Riseley, Jessica R., additional, Stephenson, Sarah E.M., additional, Fitzpatrick, Elizabeth, additional, Haas, Stefan A., additional, Pope, Kate, additional, Hogan, Kirk J., additional, Gregg, Ronald G., additional, Bromhead, Catherine J., additional, Wargowski, David S., additional, Lawrence, Christopher H., additional, James, Paul A., additional, Churchyard, Andrew, additional, Gao, Yujing, additional, Phelan, Dean G., additional, Gillies, Greta, additional, Salce, Nicholas, additional, Stanford, Lynn, additional, Marsh, Ashley P.L., additional, Mignogna, Maria L., additional, Hayflick, Susan J., additional, Leventer, Richard J., additional, Delatycki, Martin B., additional, Mellick, George D., additional, Kalscheuer, Vera M., additional, D’Adamo, Patrizia, additional, Bahlo, Melanie, additional, Amor, David J., additional, and Lockhart, Paul J., additional

Published
2014
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13. Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency

Author

Sim, Joe C H, primary, White, Susan M, additional, Fitzpatrick, Elizabeth, additional, Wilson, Gabrielle R, additional, Gillies, Greta, additional, Pope, Kate, additional, Mountford, Hayley S, additional, Torring, Pernille M, additional, McKee, Shane, additional, Vulto-van Silfhout, Anneke T, additional, Jhangiani, Shalini N, additional, Muzny, Donna M, additional, Leventer, Richard J, additional, Delatycki, Martin B, additional, Amor, David J, additional, and Lockhart, Paul J, additional

Published
2014
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14. The role of the Parkin Co-Regulated Gene (PACRG) in male infertility

Author

Wilson, Gabrielle R. and Wilson, Gabrielle R.

Abstract

A leading cause of male infertility is genetic variation in genes required for sperm formation and/or function. There is evidence to suggest PACRG is involved in mammalian spermatogenesis. Specifically, the loss of Pacrg function causes a spermatogenic defect and male infertility in mice. To investigate if PACRG plays a similar role in human spermatogenesis, the localisation of PACRG was determined in human testis. Using an immunohistochemical approach, this study demonstrated that PACRG is localised to the human sperm flagella. To investigate a potential role for PACRG in human male infertility, sequence analysis and an association study were performed. Sequence analysis did not identify any pathological alterations. However, 1 of 3 variants identified (rs9347683) was shown to be significantly associated with male infertility by association analysis (p=0.009, Odds Ratio=1.6, n=766). A high degree of structural and functional conservation exists between different types of motile cilia/flagella. Evidence from studies in C.reinhardtii and T.brucei indicate Pacrg is necessary for axoneme formation and microtubule stability. To test the role of the mammalian homologue, this study characterised the Pacrg knockout mouse, quakingviable (qkv) and generated Pacrg transgenic qkv mice (qkv-Tg). Using immunohistochemistry and immunoelectron microscopy this study demonstrated that Pacrg was localised to the axonemal microtubule doublets of sperm and ependymal cilia. The absence of Pacrg was associated with compromised sperm flagella formation and male infertility. In addition, histological and MRI analysis of qkv mutant mice revealed hydrocephalus. Specifically, qkv mutant mice showed a ~2.5 fold expansion of the lateral ventricle area compared to wildtype mice. The hydrocephalus phenotype was associated with a reduction in ependymal cilial beat frequency (CBF). Transgenic expression of Pacrg was sufficient to rescue the hydrocephalus and infertility phenotypes. In conclusion, t

Published
2009

15. Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome

Author

Wilson, Gabrielle R, primary, Sunley, Jasmine, additional, Smith, Katherine R, additional, Pope, Kate, additional, Bromhead, Catherine J, additional, Fitzpatrick, Elizabeth, additional, Di Rocco, Maja, additional, van Steensel, Maurice, additional, Coman, David J, additional, Leventer, Richard J, additional, Delatycki, Martin B, additional, Amor, David J, additional, Bahlo, Melanie, additional, and Lockhart, Paul J, additional

Published
2013
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16. ironXS: high-school screening for hereditary haemochromatosis is acceptable and feasible

Author

Delatycki, Martin B, primary, Wolthuizen, Michelle, additional, Collins, Veronica, additional, Varley, Elizabeth, additional, Craven, Joanna, additional, Allen, Katrina J, additional, Gurrin, Lyle C, additional, Aitken, Maryanne, additional, Trembath, M Kaye, additional, Bond, Lyndal, additional, Wilson, Gabrielle R, additional, Stephenson, Sarah EM, additional, Macciocca, Ivan, additional, Hickerton, Chriselle, additional, Lockhart, Paul J, additional, and Metcalfe, Sylvia A, additional

Published
2012
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17. Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome.

Author

Wilson, Gabrielle R, Sunley, Jasmine, Smith, Katherine R, Pope, Kate, Bromhead, Catherine J, Fitzpatrick, Elizabeth, Di Rocco, Maja, van Steensel, Maurice, Coman, David J, Leventer, Richard J, Delatycki, Martin B, Amor, David J, Bahlo, Melanie, and Lockhart, Paul J

Subjects
*GENETIC mutation, *MITRAL valve prolapse, *MITRAL valve diseases, *GENETIC code, *GENETIC disorders
Abstract

Borrone Dermato-Cardio-Skeletal (BDCS) syndrome is a severe progressive autosomal recessive disorder characterized by coarse facies, thick skin, acne conglobata, dysmorphic facies, vertebral abnormalities and mitral valve prolapse. We identified a consanguineous kindred with a child clinically diagnosed with BDCS. Linkage analysis of this family (BDCS1) identified five regions homozygous by descent with a maximum LOD score of 1.75. Linkage analysis of the family that originally defined BDCS (BDCS3) identified an overlapping linkage peak at chromosome 5q35.1. Sequence analysis identified two different homozygous mutations in BDCS1 and BDCS3, affecting the gene encoding the protein SH3 and PX domains 2B (SH3PXD2B), which localizes to 5q35.1. Western blot analysis of patient fibroblasts derived from affected individuals in both families demonstrated complete loss of SH3PXD2B. Homozygosity mapping and sequence analysis in a second published BDCS family (BDCS2) excluded SH3PXD2B. SH3PXD2B is required for the formation of functional podosomes, and loss-of-function mutations in SH3PXD2B have recently been shown to underlie 7 of 13 families with Frank-Ter Haar syndrome (FTHS). FTHS and BDCS share some overlapping clinical features; therefore, our results demonstrate that a proportion of BDCS and FTHS cases are allelic. Mutations in other gene(s) functioning in podosome formation and regulation are likely to underlie the SH3PXD2B-mutation-negative BDSC/FTHS patients. [ABSTRACT FROM AUTHOR]

Published
2014
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18. Additional file 1 of Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

Author

Yujing Gao, Wilson, Gabrielle R., Stephenson, Sarah E. M., Oulad-Abdelghani, Mustapha, Charlet-Berguerand, Nicolas, Kiymet Bozaoglu, McLean, Catriona A., Thomas, Paul Q., Finkelstein, David I., and Lockhart, Paul J.

Subjects
3. Good health
Abstract

Additional file 1: Table S1. Predicted CRISPR/Cas9 targets and off- targets. Table S2. Genotyping primers. Table S3. Riboprobe primers.

19. Additional file 1 of Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

Author

Yujing Gao, Wilson, Gabrielle R., Stephenson, Sarah E. M., Oulad-Abdelghani, Mustapha, Charlet-Berguerand, Nicolas, Kiymet Bozaoglu, McLean, Catriona A., Thomas, Paul Q., Finkelstein, David I., and Lockhart, Paul J.

Subjects
3. Good health
Abstract

Additional file 1: Table S1. Predicted CRISPR/Cas9 targets and off- targets. Table S2. Genotyping primers. Table S3. Riboprobe primers.

20. Experimental autoimmune Goodpasture's disease: a pathogenetic role for both effector cells and antibody in injury.

Author

Dean EG, Wilson GR, Li M, Edgtton KL, O'Sullivan KM, Hudson BG, Holdsworth SR, and Kitching AR

Subjects
Animals, Anti-Glomerular Basement Membrane Disease immunology, Antibodies toxicity, Autoantibodies, Glomerulonephritis etiology, Male, Mice, Mice, Inbred C57BL, Proteinuria etiology, Anti-Glomerular Basement Membrane Disease etiology, Antibodies physiology, B-Lymphocytes physiology
Abstract

Background: Goodpasture's disease [antiglomerular basement membrane (GBM) glomerulonephritis] is a classic autoimmune disease and the only organ-specific autoimmune renal disease in which the antigen is well described. The importance of antibodies against the non-collagenous domain of the alpha3 chain of type IV collagen [alpha3(IV)NC1] is well established. However, observational human studies and studies in experimental systems also imply a role for cell-mediated effector injury., Methods: Active experimental autoimmune glomerulonephritis (EAG) was induced by immunization with alpha3-alpha5(IV)NC1 heterodimers in B cell intact C57BL/6 mice and B cell (mu chain-deficient) mice. Passive disease was induced by transferring sera from B cell intact and B cell deficient mice with EAG to RAG-1-/- mice (that lack adaptive immunity). Histologic and functional injury was studied., Results: Despite the absence of B cells and immunoglobulin in B-cell-deficient mice, histologic and functional injury developed in mice immunized with alpha3-alpha5(IV)NC1, with T cells and macrophages in glomeruli. Injury occurred to a similar degree to that found in B-cell-intact mice. Transfer of sera from B-cell-intact mice with EAG containing antibodies (but not from B-cell-deficient mice with EAG) to RAG-1-/- mice induced linear immunoglobulin deposits on the glomerular basement membrane (GBM) and pathologic proteinuria., Conclusion: Both cell-mediated and humoral effectors are capable of inducing renal injury in EAG. Given the similarity of the disease-initiating antigen in this model to the antigen in human anti-GBM glomerulonephritis, similar overlapping mechanisms are likely to operate in human disease.

Published
2005
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