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6 results on '"Carss, K.J."'

1. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans

Author

Tuijnenburg, P., Lango Allen, H., Burns, S.O., Greene, D., Jansen, M.H., Staples, E., Stephens, J., Carss, K.J., Biasci, D., Baxendale, H., Thomas, M., Chandra, A., Kiani-Alikhan, S., Longhurst, H.J., Seneviratne, S.L., Oksenhendler, E., Simeoni, I., de Bree, G.J., Tool, A.T.J., van Leeuwen, E.M.M., Ebberink, E.H.T.M., Meijer, A.B., Tuna, S., Whitehorn, D., Brown, M., Turro, E., Thrasher, A.J., Smith, K.G.C., Thaventhiran, J.E., Kuijpers, T.W., Adhya, Z., Alachkar, H., Anantharachagan, A., Antrobus, R., Arumugakani, G., Bacchelli, C., Bethune, C., Bibi, S., Boardman, B., Booth, C., Browning, M., Brownlie, M., Burns, S., Clifford, H., Cooper, N., Davies, S., Dempster, J., Devlin, L., Doffinger, R., Drewe, E., Edgar, D., Egner, W., El-Shanawany, T., Gaspar, B., Ghurye, R., Gilmour, K., Goddard, S., Gordins, P., Grigoriadou, S., Hackett, S., Hague, R., Harper, L., Hayman, G., Herwadkar, A., Hughes, S., Huissoon, A., Jolles, S., Jones, J., Kelleher, P., Klein, N., Kuijpers, T., Kumararatne, D., Laffan, J., Allen, H.L., Lear, S., Longhurst, H., Lorenzo, L., Maimaris, J., Manson, A., McDermott, E., Millar, H., Mistry, A., Morrisson, V., Murng, S., Nasir, I., and Nejentsev, S.

Abstract

Background: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. Objective: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort. Methods: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. Results: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21lowB-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. Conclusion: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

Published
2018

2. Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides

Author

Sangermano, R, Garanto, A., Khan, M. (Mubeen), Runhart, E.H., Bauwens, M., Bax, N.M.A. (Klaas), Born, L.I. (Ingeborgh) van den, Khan, M.I. (Muhammad), Cornelis, S.S., Verheij, J, Pott, J.W.R., Thiadens, A., Klaver, C.C.W. (Caroline), Puech, B., Meunier, I., Naessens, S., Arno, G., Fakin, A., Carss, K.J., Raymond, FL, Webster, A.R. (Andrew), Dhaenens, C.M., Stohr, H., Grassmann, F. (Felix), Weber, B.H.F. (Bernhard), Hoyng, C.B. (Carel), De Baere, E. (Elfride), Albert, S., Collin, R.W.J. (Rob), Cremers, F.P.M. (Frans), Sangermano, R, Garanto, A., Khan, M. (Mubeen), Runhart, E.H., Bauwens, M., Bax, N.M.A. (Klaas), Born, L.I. (Ingeborgh) van den, Khan, M.I. (Muhammad), Cornelis, S.S., Verheij, J, Pott, J.W.R., Thiadens, A., Klaver, C.C.W. (Caroline), Puech, B., Meunier, I., Naessens, S., Arno, G., Fakin, A., Carss, K.J., Raymond, FL, Webster, A.R. (Andrew), Dhaenens, C.M., Stohr, H., Grassmann, F. (Felix), Weber, B.H.F. (Bernhard), Hoyng, C.B. (Carel), De Baere, E. (Elfride), Albert, S., Collin, R.W.J. (Rob), and Cremers, F.P.M. (Frans)

Abstract

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

Published
2019
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3. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., Lerche, H., et al., Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., and Lerche, H., et al.

Abstract

Item does not contain fulltext, Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

4. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author

Ito, Y., Carss, K.J., Duarte, S.T., Hartley, T., Keren, B., Kurian, M.A., Marey, I., Charles, P., Mendonca, C., Nava, C., Pfundt, R.P., Sanchis-Juan, A., Bokhoven, H. van, Essen, A. van, Ravenswaaij-Arts, C.M.A. van, Boycott, K.M., Kernohan, K.D., Dyack, S., Raymond, F.L., Ito, Y., Carss, K.J., Duarte, S.T., Hartley, T., Keren, B., Kurian, M.A., Marey, I., Charles, P., Mendonca, C., Nava, C., Pfundt, R.P., Sanchis-Juan, A., Bokhoven, H. van, Essen, A. van, Ravenswaaij-Arts, C.M.A. van, Boycott, K.M., Kernohan, K.D., Dyack, S., and Raymond, F.L.

Abstract

Contains fulltext : 196206.pdf (Publisher’s version ) (Open Access), Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.

Published
2018

5. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Author

Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M., Grozeva, D., Joseph, A.P., Mencacci, N.E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M.A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J.A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S.S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K.J., Peters, G.B., Prabhakar, P., Reuter, M.S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S.M., Wieczorek, D., Wiethoff, S., Wilson, B.T., Winter, G., Wragg, C., Pope, S., Heales, S.J., Morrogh, D., Pittman, A., Carr, L.J., Perez-Duenas, B., Lin, J.P., Reis, A., Gahl, W.A., Toro, C., Bhatia, K.P., Wood, N.W., Kamsteeg, E.J., Chong, W.K., Gissen, P., Topf, M., Dale, R.C., Chubb, J.R., Raymond, F.L., Kurian, M.A., Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M., Grozeva, D., Joseph, A.P., Mencacci, N.E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M.A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J.A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S.S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K.J., Peters, G.B., Prabhakar, P., Reuter, M.S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S.M., Wieczorek, D., Wiethoff, S., Wilson, B.T., Winter, G., Wragg, C., Pope, S., Heales, S.J., Morrogh, D., Pittman, A., Carr, L.J., Perez-Duenas, B., Lin, J.P., Reis, A., Gahl, W.A., Toro, C., Bhatia, K.P., Wood, N.W., Kamsteeg, E.J., Chong, W.K., Gissen, P., Topf, M., Dale, R.C., Chubb, J.R., Raymond, F.L., and Kurian, M.A.

Abstract

Item does not contain fulltext, Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Published
2017

6. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of alpha-dystroglycan

Author

Carss, K.J., Stevens, E., Foley, A.R., Cirak, S., Riemersma, M., Torelli, S., Hoischen, A., Willer, T., Scherpenzeel, M. van, Moore, S.A., Messina, S., Bertini, E., Bonnemann, C.G., Abdenur, J.E., Grosmann, C.M., Kesari, A., Punetha, J., Quinlivan, R., Waddell, L.B., Young, H.K., Wraige, E., Yau, S., Brodd, L., Feng, L., Sewry, C., MacArthur, D.G., North, K.N., Hoffman, E., Stemple, D.L., Hurles, M.E., Bokhoven, H. van, Campbell, K.P., Lefeber, D.J., Lin, Y.Y., Muntoni, F., et al., Carss, K.J., Stevens, E., Foley, A.R., Cirak, S., Riemersma, M., Torelli, S., Hoischen, A., Willer, T., Scherpenzeel, M. van, Moore, S.A., Messina, S., Bertini, E., Bonnemann, C.G., Abdenur, J.E., Grosmann, C.M., Kesari, A., Punetha, J., Quinlivan, R., Waddell, L.B., Young, H.K., Wraige, E., Yau, S., Brodd, L., Feng, L., Sewry, C., MacArthur, D.G., North, K.N., Hoffman, E., Stemple, D.L., Hurles, M.E., Bokhoven, H. van, Campbell, K.P., Lefeber, D.J., Lin, Y.Y., Muntoni, F., and et al.

Abstract

Item does not contain fulltext, Congenital muscular dystrophies with hypoglycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of alpha-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated alpha-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including alpha-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced alpha-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of alpha-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of alpha-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of alpha-DG.

Published
2013

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