7 results on '"Friend K.L."'
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2. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
- Author
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Hu, H, Haas, S.A., Chelly, J., Esch, H. Van, Raynaud, M., Brouwer, A.P. de, Weinert, S., Froyen, G., Frints, S.G., Laumonnier, F., Zemojtel, T., Love, M.I., Richard, H., Emde, A.K., Bienek, M., Jensen, C., Hambrock, M., Fischer, U., Langnick, C., Feldkamp, M., Wissink, W.M., Lebrun, N., Castelnau, L., Rucci, J., Montjean, R., Dorseuil, O., Billuart, P., Stuhlmann, T., Shaw, M., Corbett, M.A., Gardner, A., Willis-Owen, S., Tan, C., Friend, K.L., Belet, S., Roozendaal, K.E. van, Jimenez-Pocquet, M., Moizard, M.P., Ronce, N., Sun, R., O'Keeffe, S., Chenna, R., Bommel, A. van, Goke, J., Hackett, A., Field, M., Christie, L., Boyle, J., Haan, E., Nelson, J., Turner, G., Baynam, G., Gillessen-Kaesbach, G., Muller, U., Steinberger, D., Budny, B., Badura-Stronka, M., Latos-Bielenska, A., Ousager, L.B., Wieacker, P., Rodriguez Criado, G., Bondeson, M.L., Anneren, G., Dufke, A., Cohen, M., Maldergem, L. Van, Vincent-Delorme, C., Echenne, B., Simon-Bouy, B., Kleefstra, T., Willemsen, M.H., Fryns, J.P., Devriendt, K., Ullmann, R., Vingron, M., Wrogemann, K., Wienker, T.F., Tzschach, A., Bokhoven, H. van, Gecz, J., Jentsch, T.J., Chen, W., Ropers, H.H., Kalscheuer, V.M., Hu, H, Haas, S.A., Chelly, J., Esch, H. Van, Raynaud, M., Brouwer, A.P. de, Weinert, S., Froyen, G., Frints, S.G., Laumonnier, F., Zemojtel, T., Love, M.I., Richard, H., Emde, A.K., Bienek, M., Jensen, C., Hambrock, M., Fischer, U., Langnick, C., Feldkamp, M., Wissink, W.M., Lebrun, N., Castelnau, L., Rucci, J., Montjean, R., Dorseuil, O., Billuart, P., Stuhlmann, T., Shaw, M., Corbett, M.A., Gardner, A., Willis-Owen, S., Tan, C., Friend, K.L., Belet, S., Roozendaal, K.E. van, Jimenez-Pocquet, M., Moizard, M.P., Ronce, N., Sun, R., O'Keeffe, S., Chenna, R., Bommel, A. van, Goke, J., Hackett, A., Field, M., Christie, L., Boyle, J., Haan, E., Nelson, J., Turner, G., Baynam, G., Gillessen-Kaesbach, G., Muller, U., Steinberger, D., Budny, B., Badura-Stronka, M., Latos-Bielenska, A., Ousager, L.B., Wieacker, P., Rodriguez Criado, G., Bondeson, M.L., Anneren, G., Dufke, A., Cohen, M., Maldergem, L. Van, Vincent-Delorme, C., Echenne, B., Simon-Bouy, B., Kleefstra, T., Willemsen, M.H., Fryns, J.P., Devriendt, K., Ullmann, R., Vingron, M., Wrogemann, K., Wienker, T.F., Tzschach, A., Bokhoven, H. van, Gecz, J., Jentsch, T.J., Chen, W., Ropers, H.H., and Kalscheuer, V.M.
- Abstract
Contains fulltext : 168284.pdf (Publisher’s version ) (Open Access), X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
- Published
- 2016
3. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
- Author
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Hu, H., Haas, S.A., Chelly, J., Van Esch, H., Raynaud, M., de Brouwer, A.P.M., Weinert, S., Froyen, G., Frints, S.G M, Laumonnier, F., Zemojtel, T., Love, M.I., Richard, H., Emde, A-K, Bienek, M., Jensen, C., Hambrock, M., Fischer, U., Langnick, C., Feldkamp, M., Wissink-Lindhout, W., Lebrun, N., Castelnau, L., Rucci, J., Montjean, R., Dorseuil, O., Billuart, P., Stuhlmann, T., Shaw, M., Corbett, M.A., Gardner, A., Willis-Owen, S., Tan, C., Friend, K.L., Belet, S., van Roozendaal, K.E.P., Jimenez-Pocquet, M., Moizard, M-P, Ronce, N., Sun, R., O'Keeffe, S., Chenna, R., van Bömmel, A., Göke, J., Hackett, A., Field, M., Christie, L., Boyle, J., Haan, E., Nelson, J., Turner, G., Baynam, G., Gillessen-Kaesbach, G., Müller, U., Steinberger, D., Budny, B., Badura-Stronka, M., Latos-Bieleńska, A., Ousager, L.B., Wieacker, P., Rodríguez Criado, G., Bondeson, M-L, Annerén, G., Dufke, A., Cohen, M., Van Maldergem, L., Vincent-Delorme, C., Echenne, B., Simon-Bouy, B., Kleefstra, T., Willemsen, M., Fryns, J-P, Devriendt, K., Ullmann, R., Vingron, M., Wrogemann, K., Wienker, T.F., Tzschach, A., van Bokhoven, H., Gecz, J., Jentsch, T.J., Chen, W., Ropers, H-H, Kalscheuer, V.M., Hu, H., Haas, S.A., Chelly, J., Van Esch, H., Raynaud, M., de Brouwer, A.P.M., Weinert, S., Froyen, G., Frints, S.G M, Laumonnier, F., Zemojtel, T., Love, M.I., Richard, H., Emde, A-K, Bienek, M., Jensen, C., Hambrock, M., Fischer, U., Langnick, C., Feldkamp, M., Wissink-Lindhout, W., Lebrun, N., Castelnau, L., Rucci, J., Montjean, R., Dorseuil, O., Billuart, P., Stuhlmann, T., Shaw, M., Corbett, M.A., Gardner, A., Willis-Owen, S., Tan, C., Friend, K.L., Belet, S., van Roozendaal, K.E.P., Jimenez-Pocquet, M., Moizard, M-P, Ronce, N., Sun, R., O'Keeffe, S., Chenna, R., van Bömmel, A., Göke, J., Hackett, A., Field, M., Christie, L., Boyle, J., Haan, E., Nelson, J., Turner, G., Baynam, G., Gillessen-Kaesbach, G., Müller, U., Steinberger, D., Budny, B., Badura-Stronka, M., Latos-Bieleńska, A., Ousager, L.B., Wieacker, P., Rodríguez Criado, G., Bondeson, M-L, Annerén, G., Dufke, A., Cohen, M., Van Maldergem, L., Vincent-Delorme, C., Echenne, B., Simon-Bouy, B., Kleefstra, T., Willemsen, M., Fryns, J-P, Devriendt, K., Ullmann, R., Vingron, M., Wrogemann, K., Wienker, T.F., Tzschach, A., van Bokhoven, H., Gecz, J., Jentsch, T.J., Chen, W., Ropers, H-H, and Kalscheuer, V.M.
- Abstract
X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
- Published
- 2016
4. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability
- Author
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Kumar, R., Corbett, M.A., Bon, B.W.M. van, Woenig, J.A., Weir, L., Douglas, E., Friend, K.L., Gardner, A., Shaw, M., Jolly, L.A., Tan, C., Hunter, M.F., Hackett, A., Field, M., Palmer, E.E., Leffler, M., Rogers, C., Boyle, J., Bienek, M., Jensen, C., Buggenhout, G. Van, Esch, H. Van, Hoffmann, K., Raynaud, M., Zhao, H., Reed, R., Hu, H, Haas, S.A., Haan, E., Kalscheuer, V.M., Gecz, J., Kumar, R., Corbett, M.A., Bon, B.W.M. van, Woenig, J.A., Weir, L., Douglas, E., Friend, K.L., Gardner, A., Shaw, M., Jolly, L.A., Tan, C., Hunter, M.F., Hackett, A., Field, M., Palmer, E.E., Leffler, M., Rogers, C., Boyle, J., Bienek, M., Jensen, C., Buggenhout, G. Van, Esch, H. Van, Hoffmann, K., Raynaud, M., Zhao, H., Reed, R., Hu, H, Haas, S.A., Haan, E., Kalscheuer, V.M., and Gecz, J.
- Abstract
Item does not contain fulltext, Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
- Published
- 2015
5. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.
- Author
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Douglas E., Bienek M., Jensen C., Van Buggenhout G., Van Esch H., Hoffmann K., Raynaud M., Zhao H., Reed R., Hu H., Haas S.A., Haan E., Kalscheuer V.M., Gecz J., Hunter M.F., Kumar R., Corbett M.A., Van Bon B.W.M., Woenig J.A., Weir L., Friend K.L., Gardner A., Shaw M., Jolly L.A., Tan C., Hackett A., Field M., Palmer E.E., Leffler M., Rogers C., Boyle J., Douglas E., Bienek M., Jensen C., Van Buggenhout G., Van Esch H., Hoffmann K., Raynaud M., Zhao H., Reed R., Hu H., Haas S.A., Haan E., Kalscheuer V.M., Gecz J., Hunter M.F., Kumar R., Corbett M.A., Van Bon B.W.M., Woenig J.A., Weir L., Friend K.L., Gardner A., Shaw M., Jolly L.A., Tan C., Hackett A., Field M., Palmer E.E., Leffler M., Rogers C., and Boyle J.
- Abstract
Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.Copyright © 2015 The American Society of Human Genetics.
- Published
- 2015
6. Refining analyses of copy number variation identifies specific genes associated with developmental delay.
- Author
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Coe, B.P., Witherspoon, K., Rosenfeld, J.A., Bon, B.W.M. van, Silfhout, A.T. van, Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E.L.M., Schuurs-Hoeijmakers, J.H.M., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G.L., Li, D., Amaral, D., Brown, N., Lockhart, P.J., Scheffer, I.E., Alberti, A., Shaw, M., Pettinato, R., Tervo, R., Leeuw, N. de, Reijnders, M.R., Torchia, B.S., Peeters, H., Thompson, E., O'Roak, B.J., Fichera, M., Hehir-Kwa, J.Y., Shendure, J., Mefford, H.C., Haan, E., Gécz, J., Vries, L.B.A. de, Romano, C, Eichler, E.E., Coe, B.P., Witherspoon, K., Rosenfeld, J.A., Bon, B.W.M. van, Silfhout, A.T. van, Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E.L.M., Schuurs-Hoeijmakers, J.H.M., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G.L., Li, D., Amaral, D., Brown, N., Lockhart, P.J., Scheffer, I.E., Alberti, A., Shaw, M., Pettinato, R., Tervo, R., Leeuw, N. de, Reijnders, M.R., Torchia, B.S., Peeters, H., Thompson, E., O'Roak, B.J., Fichera, M., Hehir-Kwa, J.Y., Shendure, J., Mefford, H.C., Haan, E., Gécz, J., Vries, L.B.A. de, Romano, C, and Eichler, E.E.
- Abstract
Contains fulltext : 136682.pdf (publisher's version ) (Closed access)
- Published
- 2014
7. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2
- Author
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Marina A. J. Tijssen, Mark A. Corbett, Zaid Afawi, Paolo Tinuper, Shoji Tsuji, Rachel Straussberg, Ilan Blatt, Samuel F. Berkovic, Francesco Brancati, Amy L Schneider, Lynette G. Sadleir, Sanjay M. Sisodiya, Renzo Guerrini, Shreyasee Chakraborty, Alfredo Berardelli, Silvana Franceschetti, Jozef Gecz, Luciano Xumerle, Pierre Labauge, Liana Veneziano, Simona Balestrini, Ingo Helbig, Martin A. Smith, Laura Canafoglia, Carlo Di Bonaventura, Hiroyuki Ishiura, Boris Keren, Manuela Pendziwiat, Rahel T. Florian, Sylvie Forlani, Anne Fleur van Rootselaar, Giorgio Casari, Christel Depienne, Tommaso Pippucci, Douglas E. Crompton, Edouard Hirsch, Davide Mei, Laura Licchetta, Renee Carroll, Riaan van Coller, Ingrid E. Scheffer, Thessa Kroes, Pasquale Striano, Brigid M. Regan, Francesca Bisulli, Shaun Carswell, Antonio Suppa, Julien Buratti, Karl Martin Klein, Alison Gardner, Caroline Nava, Federico Zara, Melanie Bahlo, Sabine Kaya, Kathryn Friend, Antonietta Coppola, Massimo Delledonne, Aaron M. Wenger, Anthony Correll, Sara Baldassari, Arn M. J. M. van den Maagdenberg, Eric LeGuern, Rachael Catford, Gabrielle Rudolf, Salvatore Striano, Mark F. Bennett, Josemir W. Sander, Kirston Barton, Michele Iacomino, Corbett M.A., Kroes T., Veneziano L., Bennett M.F., Florian R., Schneider A.L., Coppola A., Licchetta L., Franceschetti S., Suppa A., Wenger A., Mei D., Pendziwiat M., Kaya S., Delledonne M., Straussberg R., Xumerle L., Regan B., Crompton D., van Rootselaar A.-F., Correll A., Catford R., Bisulli F., Chakraborty S., Baldassari S., Tinuper P., Barton K., Carswell S., Smith M., Berardelli A., Carroll R., Gardner A., Friend K.L., Blatt I., Iacomino M., Di Bonaventura C., Striano S., Buratti J., Keren B., Nava C., Forlani S., Rudolf G., Hirsch E., Leguern E., Labauge P., Balestrini S., Sander J.W., Afawi Z., Helbig I., Ishiura H., Tsuji S., Sisodiya S.M., Casari G., Sadleir L.G., van Coller R., Tijssen M.A.J., Klein K.M., van den Maagdenberg A.M.J.M., Zara F., Guerrini R., Berkovic S.F., Pippucci T., Canafoglia L., Bahlo M., Striano P., Scheffer I.E., Brancati F., Depienne C., Gecz J., Neurology, ANS - Brain Imaging, Movement Disorder (MD), Corbett, M. A., Kroes, T., Veneziano, L., Bennett, M. F., Florian, R., Schneider, A. L., Coppola, A., Licchetta, L., Franceschetti, S., Suppa, A., Wenger, A., Mei, D., Pendziwiat, M., Kaya, S., Delledonne, M., Straussberg, R., Xumerle, L., Regan, B., Crompton, D., van Rootselaar, A. -F., Correll, A., Catford, R., Bisulli, F., Chakraborty, S., Baldassari, S., Tinuper, P., Barton, K., Carswell, S., Smith, M., Berardelli, A., Carroll, R., Gardner, A., Friend, K. L., Blatt, I., Iacomino, M., Di Bonaventura, C., Striano, S., Buratti, J., Keren, B., Nava, C., Forlani, S., Rudolf, G., Hirsch, E., Leguern, E., Labauge, P., Balestrini, S., Sander, J. W., Afawi, Z., Helbig, I., Ishiura, H., Tsuji, S., Sisodiya, S. M., Casari, G., Sadleir, L. G., van Coller, R., Tijssen, M. A. J., Klein, K. M., van den Maagdenberg, A. M. J. M., Zara, F., Guerrini, R., Berkovic, S. F., Pippucci, T., Canafoglia, L., Bahlo, M., Striano, P., Scheffer, I. E., Brancati, F., Depienne, C., and Gecz, J.
- Subjects
0301 basic medicine ,Male ,Myoclonus ,Medizin ,General Physics and Astronomy ,Epilepsies, Myoclonic ,Epilepsies ,Intronic variant, repeat expansions,STARD7, familial adult myoclonic epilepsy, chromosome 2 ,Epilepsy ,0302 clinical medicine ,DOMINANT CORTICAL TREMOR ,EXPRESSION ANALYSIS ,PEDIGREE ,LOCUS ,LINKAGE ,GENE ,2P11.1-Q12.2 ,REFINEMENT ,MUTATION ,BAFME ,lcsh:Science ,Child ,Genetics ,Multidisciplinary ,DNA Repeat Expansion ,Disease genetics ,Chromosome Mapping ,Middle Aged ,Pedigree ,Myoclonic Epilepsy ,Child, Preschool ,Chromosomes, Human, Pair 2 ,Pair 2 ,STARD7 ,Female ,Adolescent ,Adult ,Carrier Proteins ,Humans ,Young Adult ,Introns ,Human ,Science ,Locus (genetics) ,Biology ,Chromosomes ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Preschool ,Gene ,Whole genome sequencing ,Intron ,Chromosome ,General Chemistry ,medicine.disease ,030104 developmental biology ,Microsatellite instability ,Myoclonic epilepsy ,lcsh:Q ,Familial Adult Myoclonic Epilepsy ,Myoclonic ,Carrier Protein ,030217 neurology & neurosurgery ,Neurological disorders - Abstract
Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved., Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”
- Published
- 2019
- Full Text
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