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Your search keyword '"Cummings, B.B."' showing total 4 results
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4 results on '"Cummings, B.B."'

1. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

Author

Bolduc, V, Foley, A.R., Solomon-Degefa, H., Sarathy, A., Donkervoort, S., Hu, Y., Chen, G.S., Sizov, K., Nalls, M., Zhou, H., Aguti, S., Cummings, B.B., Lek, M., Tukiainen, T., Marshall, J.L., Regev, O., Marek-Yagel, D., Sarkozy, A., Butterfield, R.J., Jou, C., Jimenez-Mallebrera, C., Li, Y., Gartioux, C., Mamchaoui, K., Allamand, V., Gualandi, F., Ferlini, A., Hanssen, E., Wilton, S.D., Lamandé, S.R., MacArthur, D.G., Wagener, R., Muntoni, F., Bönnemann, C.G., Bolduc, V, Foley, A.R., Solomon-Degefa, H., Sarathy, A., Donkervoort, S., Hu, Y., Chen, G.S., Sizov, K., Nalls, M., Zhou, H., Aguti, S., Cummings, B.B., Lek, M., Tukiainen, T., Marshall, J.L., Regev, O., Marek-Yagel, D., Sarkozy, A., Butterfield, R.J., Jou, C., Jimenez-Mallebrera, C., Li, Y., Gartioux, C., Mamchaoui, K., Allamand, V., Gualandi, F., Ferlini, A., Hanssen, E., Wilton, S.D., Lamandé, S.R., MacArthur, D.G., Wagener, R., Muntoni, F., and Bönnemann, C.G.

Abstract

The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI–related dystrophy (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen α1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splice-modulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.

Published
2019

2. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

3. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

4. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

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