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7 results on '"Gecz, J. (Jozef)"'

1. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Author

Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), Xia, K. (Kun), Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), and Xia, K. (Kun)

Abstract

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely genedisrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITSCLIP revealed that Csde1binding targets are enriched in autismassociated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity–related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autismrelated syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

Published
2019
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2. Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

Author

Jackson, M. R. (Matilda R.), Loring, K. E. (Karagh E.), Homan, C. C. (Claire C.), Thai, M. H. (Monica H. N.), Määttänen, L. (Laura), Arvio, M. (Maria), Jarvela, I. (Irma), Shaw, M. (Marie), Gardner, A. (Alison), Gecz, J. (Jozef), Shoubridge, C. (Cheryl), Jackson, M. R. (Matilda R.), Loring, K. E. (Karagh E.), Homan, C. C. (Claire C.), Thai, M. H. (Monica H. N.), Määttänen, L. (Laura), Arvio, M. (Maria), Jarvela, I. (Irma), Shaw, M. (Marie), Gardner, A. (Alison), Gecz, J. (Jozef), and Shoubridge, C. (Cheryl)

Abstract

Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9–edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.

Published
2019

3. Genetic or other causation should not change the clinical diagnosis of cerebral palsy

Author

MacLennan, A. H. (Alastair H.), Lewis, S. (Sara), Moreno-De-Luca, A. (Andres), Fahey, M. (Michael), Leventer, R. J. (Richard J.), McIntyre, S. (Sarah), Ben-Pazi, H. (Hilla), Corbett, M. (Mark), Wang, X. (Xiaoyang), Baynam, G. (Gareth), Fehlings, D. (Darcy), Kurian, M. A. (Manju A.), Zhu, C. (Changlian), Himmelmann, K. (Kate), Smithers-Sheedy, H. (Hayley), Wilson, Y. (Yana), Ocaña, C. S. (Carlos Santos), van Eyk, C. (Clare), Badawi, N. (Nadia), Wintle, R. F. (Richard F.), Jacobsson, B. (Bo), Amor, D. J. (David J.), Mallard, C. (Carina), Pérez-Jurado, L. A. (Luis A.), Hallman, M. (Mikko), Rosenbaum, P. J. (Peter J.), Kruer, M. C. (Michael C.), Gecz, J. (Jozef), MacLennan, A. H. (Alastair H.), Lewis, S. (Sara), Moreno-De-Luca, A. (Andres), Fahey, M. (Michael), Leventer, R. J. (Richard J.), McIntyre, S. (Sarah), Ben-Pazi, H. (Hilla), Corbett, M. (Mark), Wang, X. (Xiaoyang), Baynam, G. (Gareth), Fehlings, D. (Darcy), Kurian, M. A. (Manju A.), Zhu, C. (Changlian), Himmelmann, K. (Kate), Smithers-Sheedy, H. (Hayley), Wilson, Y. (Yana), Ocaña, C. S. (Carlos Santos), van Eyk, C. (Clare), Badawi, N. (Nadia), Wintle, R. F. (Richard F.), Jacobsson, B. (Bo), Amor, D. J. (David J.), Mallard, C. (Carina), Pérez-Jurado, L. A. (Luis A.), Hallman, M. (Mikko), Rosenbaum, P. J. (Peter J.), Kruer, M. C. (Michael C.), and Gecz, J. (Jozef)

Abstract

High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as “cerebral palsy.” This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.

Published
2019

4. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

Author

Eggers, S. (Stefanie), Sadedin, S. (Simon), van den Bergen, J.A. (Jocelyn A.), Robevska, G. (Gorjana), Ohnesorg, T. (Thomas), Hewitt, J. (Joanne), Lambeth, L. (Luke), Bouty, A. (Aurore), Knarston, I.M. (Ingrid M.), Tan, T.Y. (Tiong Yang), Cameron, F.J. (Fergus), Werther, G. (George), Hutson, J. (John), O'Connell, M. (Michele), Grover, S.R. (Sonia R.), Heloury, Y. (Yves), Zacharin, M. (Margaret), Bergman, P. (Philip), Kimber, C. (Chris), Brown, J. (Justin), Webb, N. (Nathalie), Hunter, M.F. (Matthew F.), Shubha Srinivasan, Titmuss, A. (Angela), Verge, C.F. (Charles F.), Mowat, D. (David), Smith, G. (Grahame), Smith, J. (Janine), Ewans, L. (Lisa), Shalhoub, C. (Carolyn), Crock, P. (Patricia), Cowell, C. (Chris), Leong, G.M. (GaryM.), Ono, M. (Makato), Lafferty, A.R. (Antony R.), Huynh, T. (Tony), Visser, U. (Uma), Choong, C.S. (Catherine S.), McKenzie, F. (Fiona), Pachter, N. (Nicholas), Thompson, E.M. (Elizabeth M.), Couper, J. (Jennifer), Baxendale, A. (Anne), Gecz, J. (Jozef), Wheeler, B.J. (Benjamin J.), Jefferies, C. (Craig), MacKenzie, K. (Karen), Hofman, P. (Paul), Carter, P. (Philippa), King, R.I. (Richard I.), Krausz, C. (Csilla), Ravenswaaij-Arts, C.M.A. (Conny) van, Looijenga, L.H.J. (Leendert), Drop, S. (Sten), Riedl, S. (Stefan), Cools, M.B.C.M. (Martine), Dawson, A. (Angelika), Juniarto, A.Z. (Achmad), Khadilkar, V. (Vaman), Khadilkar, A. (Anuradha), Bhatia, V. (Vijayalakshmi), Dũng, V.C. (Vũ Chí), Atta, I. (Irum), Raza, J. (Jamal), thi Diem Chi, N. (Nguyen), Hao, T.K. (Tran Kiem), Harley, V.R. (Vincent), Koopman, P. (Peter), Warne, G. (Garry), Faradz, S.M.H. (Sultana), Oshlack, A. (Alicia), Ayers, K.L. (Katie L.), Sinclair, A. (Andrew), Eggers, S. (Stefanie), Sadedin, S. (Simon), van den Bergen, J.A. (Jocelyn A.), Robevska, G. (Gorjana), Ohnesorg, T. (Thomas), Hewitt, J. (Joanne), Lambeth, L. (Luke), Bouty, A. (Aurore), Knarston, I.M. (Ingrid M.), Tan, T.Y. (Tiong Yang), Cameron, F.J. (Fergus), Werther, G. (George), Hutson, J. (John), O'Connell, M. (Michele), Grover, S.R. (Sonia R.), Heloury, Y. (Yves), Zacharin, M. (Margaret), Bergman, P. (Philip), Kimber, C. (Chris), Brown, J. (Justin), Webb, N. (Nathalie), Hunter, M.F. (Matthew F.), Shubha Srinivasan, Titmuss, A. (Angela), Verge, C.F. (Charles F.), Mowat, D. (David), Smith, G. (Grahame), Smith, J. (Janine), Ewans, L. (Lisa), Shalhoub, C. (Carolyn), Crock, P. (Patricia), Cowell, C. (Chris), Leong, G.M. (GaryM.), Ono, M. (Makato), Lafferty, A.R. (Antony R.), Huynh, T. (Tony), Visser, U. (Uma), Choong, C.S. (Catherine S.), McKenzie, F. (Fiona), Pachter, N. (Nicholas), Thompson, E.M. (Elizabeth M.), Couper, J. (Jennifer), Baxendale, A. (Anne), Gecz, J. (Jozef), Wheeler, B.J. (Benjamin J.), Jefferies, C. (Craig), MacKenzie, K. (Karen), Hofman, P. (Paul), Carter, P. (Philippa), King, R.I. (Richard I.), Krausz, C. (Csilla), Ravenswaaij-Arts, C.M.A. (Conny) van, Looijenga, L.H.J. (Leendert), Drop, S. (Sten), Riedl, S. (Stefan), Cools, M.B.C.M. (Martine), Dawson, A. (Angelika), Juniarto, A.Z. (Achmad), Khadilkar, V. (Vaman), Khadilkar, A. (Anuradha), Bhatia, V. (Vijayalakshmi), Dũng, V.C. (Vũ Chí), Atta, I. (Irum), Raza, J. (Jamal), thi Diem Chi, N. (Nguyen), Hao, T.K. (Tran Kiem), Harley, V.R. (Vincent), Koopman, P. (Peter), Warne, G. (Garry), Faradz, S.M.H. (Sultana), Oshlack, A. (Alicia), Ayers, K.L. (Katie L.), and Sinclair, A. (Andrew)

Abstract

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively p

Published
2016
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5. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), Kleefstra, T. (Tjitske), Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), and Kleefstra, T. (Tjitske)

Abstract

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected

Published
2016
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6. Mutations in the nuclear localization sequence of the Aristaless related homeobox; Sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division

Author

Shoubridge, C. (Cheryl), Tan, M. (May), Fullston, T. (Tod), Cloosterman, D. (Desiree), Coman, D. (David), McGillivray, G. (George), Mancini, G.M.S. (Grazia), Kleefstra, T. (Tjitske), Gecz, J. (Jozef), Shoubridge, C. (Cheryl), Tan, M. (May), Fullston, T. (Tod), Cloosterman, D. (Desiree), Coman, D. (David), McGillivray, G. (George), Mancini, G.M.S. (Grazia), Kleefstra, T. (Tjitske), and Gecz, J. (Jozef)

Abstract

Background. Aristaless related homeobox (ARX) is a paired-type homeobox gene. ARX function is frequently affected by naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX cause a range of intellectual disability and epilepsy phenotypes with or without additional features including hand dystonia, lissencephaly, autism or dysarthria. Severe malformation phenotypes, such as X-linked lissencephaly with ambiguous genitalia (XLAG), are frequently observed in individuals with protein truncating or missense mutations clustered in the highly conserved paired-type homeodomain. Results. We have identified two novel point mutations in the R379 residue of the ARX homeodomain; c.1135C>A, p.R379S in a patient with infantile spasms and intellectual disability and c.1136G>T, p.R379L in a patient with XLAG. We investigated these and other missense mutations (R332P, R332H, R332C, T333N: associated with XLAG and Proud syndrome) predicted to affect the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain. The NLS regions are required for correct nuclear import facilitated by Importin 13 (IPO13). We demonstrate that missense mutations in either the N- or C-terminal NLS regions of the homeodomain cause significant disruption to nuclear

Published
2010
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7. PHF6 mutations in T-cell acute lymphoblastic leukemia

Author

Vlierberghe, P. (Pieter) van, Palomero, T. (Teresa), Khiabanian, H. (Hossein), Meulen, J. (Joni) van der, Castillo, M. (Mireia), Roy, N. (Nadine) van, Moerloose, B. (Barbara) de, Philippé, J. (Jan), González-García, S. (Sara), Toribio, M.L. (María), Taghon, T. (Tom), Zuurbier, L.C. (Linda), Cauwelier, B. (Barbara), Harrison, C.J. (Christine), Schwab, C. (Claire), Pisecker, M. (Markus), Strehl, S., Langerak, A.W. (Anton), Gecz, J. (Jozef), Sonneveld, E. (Edwin), Pieters, R. (Rob), Paietta, E. (Elisabeth), Rowe, J. (Jacob), Wiernik, P.H. (Peter), Benoit, Y. (Yves), Soulier, J. (Jean), Poppe, B. (Bruce), Yao, X. (Xiaopan), Cordon-Cardo, C. (Carlos), Meijerink, J.P.P. (Jules), Rabadan, R. (Raul), Speleman, F. (Franki), Ferrando, A.A. (Adolfo), Vlierberghe, P. (Pieter) van, Palomero, T. (Teresa), Khiabanian, H. (Hossein), Meulen, J. (Joni) van der, Castillo, M. (Mireia), Roy, N. (Nadine) van, Moerloose, B. (Barbara) de, Philippé, J. (Jan), González-García, S. (Sara), Toribio, M.L. (María), Taghon, T. (Tom), Zuurbier, L.C. (Linda), Cauwelier, B. (Barbara), Harrison, C.J. (Christine), Schwab, C. (Claire), Pisecker, M. (Markus), Strehl, S., Langerak, A.W. (Anton), Gecz, J. (Jozef), Sonneveld, E. (Edwin), Pieters, R. (Rob), Paietta, E. (Elisabeth), Rowe, J. (Jacob), Wiernik, P.H. (Peter), Benoit, Y. (Yves), Soulier, J. (Jean), Poppe, B. (Bruce), Yao, X. (Xiaopan), Cordon-Cardo, C. (Carlos), Meijerink, J.P.P. (Jules), Rabadan, R. (Raul), Speleman, F. (Franki), and Ferrando, A.A. (Adolfo)

Abstract

Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

Published
2010
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