X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Leanne M. Dibbens; Patrick S. Tarpey; Kim Hynes; Marta A. Bayly; Ingrid E. Scheffer; Raffaella Smith; Jamee Bomar; Edwina Sutton; Lucianne Vandeleur; Cheryl Shoubridge; Sarah Edkins; Samantha J. Turner; Claire Stevens; Sarah O'Meara; Calli Tofts; Syd Barthorpe; Gemma Buck; Jennifer Cole; Kelly Halliday; David Jones; Rebecca Lee; Mark Madison; Tatiana Mironenko; Jennifer Varian; Sofie West; Sara Widaa; Paul Wray; John Teague; Ed Dicks; Adam Butler; Andrew Menzies; Andrew Jenkinson; Rebecca Shepherd; James F. Gusella; Zaid Afawi; Aziz Mazarib; Miriam Y. Neufeld; Sara Kivity; Dorit Lev; Tally Lerman-Sagie; Amos D. Korczyn; Christopher P. Derry; Grant R. Sutherland; Kathryn Friend; Marie Shaw; Mark Corbett; Hyung Goo Kim; Daniel H. Geschwind; Paul Thomas; Eric Haan; Stephen Ryan; Shane McKee; Samuel F. Berkovic; P. Andrew Futreal; Michael R. Stratton; John C. Mulley; Jozef Gécz

doi:10.1038/ng.149

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Leanne M. Dibbens, Patrick S. Tarpey, Kim Hynes, Marta A. Bayly, Ingrid E. Scheffer, Raffaella Smith, Jamee Bomar, Edwina Sutton, Lucianne Vandeleur, Cheryl Shoubridge, Sarah Edkins, Samantha J. Turner, Claire Stevens, Sarah O'Meara, Calli Tofts, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kelly Halliday, David JonesRebecca Lee, Mark Madison, Tatiana Mironenko, Jennifer Varian, Sofie West, Sara Widaa, Paul Wray, John Teague, Ed Dicks, Adam Butler, Andrew Menzies, Andrew Jenkinson, Rebecca Shepherd, James F. Gusella, Zaid Afawi, Aziz Mazarib, Miriam Y. Neufeld, Sara Kivity, Dorit Lev, Tally Lerman-Sagie, Amos D. Korczyn, Christopher P. Derry, Grant R. Sutherland, Kathryn Friend, Marie Shaw, Mark Corbett, Hyung Goo Kim, Daniel H. Geschwind, Paul Thomas, Eric Haan, Stephen Ryan, Shane McKee, Samuel F. Berkovic, P. Andrew Futreal, Michael R. Stratton, John C. Mulley, Jozef Gécz

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Abstract

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

Original language	English
Pages (from-to)	776-781
Number of pages	6
Journal	Nature Genetics
Volume	40
Issue number	6
DOIs	https://doi.org/10.1038/ng.149
State	Published - Jun 2008
Externally published	Yes

Funding

Funders	Funder number
Australian National Health and Medical Research Council	400121
National Institute of Mental Health U.S.	R01 MH 64547
Thyne-Reid Charitable Trusts
National Institutes of Health
National Institute of General Medical Sciences	P01GM061354
National Institute of Child Health and Human Development	NO1-HD-4-3383, NO1-HD-4-3368
University of Maryland
Wellcome Trust

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Dibbens, L. M., Tarpey, P. S., Hynes, K., Bayly, M. A., Scheffer, I. E., Smith, R., Bomar, J., Sutton, E., Vandeleur, L., Shoubridge, C., Edkins, S., Turner, S. J., Stevens, C., O'Meara, S., Tofts, C., Barthorpe, S., Buck, G., Cole, J., Halliday, K., ... Gécz, J. (2008). X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nature Genetics, 40(6), 776-781. https://doi.org/10.1038/ng.149

@article{44658fea31f6495ca9d0999f788a0cbd,

title = "X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment",

abstract = "Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.",

author = "Dibbens, {Leanne M.} and Tarpey, {Patrick S.} and Kim Hynes and Bayly, {Marta A.} and Scheffer, {Ingrid E.} and Raffaella Smith and Jamee Bomar and Edwina Sutton and Lucianne Vandeleur and Cheryl Shoubridge and Sarah Edkins and Turner, {Samantha J.} and Claire Stevens and Sarah O'Meara and Calli Tofts and Syd Barthorpe and Gemma Buck and Jennifer Cole and Kelly Halliday and David Jones and Rebecca Lee and Mark Madison and Tatiana Mironenko and Jennifer Varian and Sofie West and Sara Widaa and Paul Wray and John Teague and Ed Dicks and Adam Butler and Andrew Menzies and Andrew Jenkinson and Rebecca Shepherd and Gusella, {James F.} and Zaid Afawi and Aziz Mazarib and Neufeld, {Miriam Y.} and Sara Kivity and Dorit Lev and Tally Lerman-Sagie and Korczyn, {Amos D.} and Derry, {Christopher P.} and Sutherland, {Grant R.} and Kathryn Friend and Marie Shaw and Mark Corbett and Kim, {Hyung Goo} and Geschwind, {Daniel H.} and Paul Thomas and Eric Haan and Stephen Ryan and Shane McKee and Berkovic, {Samuel F.} and Futreal, {P. Andrew} and Stratton, {Michael R.} and Mulley, {John C.} and Jozef G{\'e}cz",

note = "Funding Information: We thank the members of the families studied for their participation and members of the International Genetics of Learning Disability (IGOLD) study for their collaboration. This work was supported by grants from the Australian National Health and Medical Research Council Program Grant 400121 (I.E.S., S.F.B., J.C.M. and J.G.), Thyne-Reid Charitable Trusts (L.M.D.) and the Wellcome Trust. We also acknowledge support to J.F.G. from US National Institutes of Health grant GM061354 and D.H.G. from US National Institute of Mental Health U.S. grant R01 MH 64547. We are grateful for access to the tissues used in these studies from the Developmental Brain and Tissue Bank at University of Maryland funded by the US National Institutes of Health (National Institute of Child Health and Human Development contracts NO1-HD-4-3368 and NO1-HD-4-3383).",

year = "2008",

month = jun,

doi = "10.1038/ng.149",

language = "אנגלית",

volume = "40",

pages = "776--781",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Dibbens, LM, Tarpey, PS, Hynes, K, Bayly, MA, Scheffer, IE, Smith, R, Bomar, J, Sutton, E, Vandeleur, L, Shoubridge, C, Edkins, S, Turner, SJ, Stevens, C, O'Meara, S, Tofts, C, Barthorpe, S, Buck, G, Cole, J, Halliday, K, Jones, D, Lee, R, Madison, M, Mironenko, T, Varian, J, West, S, Widaa, S, Wray, P, Teague, J, Dicks, E, Butler, A, Menzies, A, Jenkinson, A, Shepherd, R, Gusella, JF, Afawi, Z, Mazarib, A, Neufeld, MY, Kivity, S, Lev, D , Lerman-Sagie, T , Korczyn, AD, Derry, CP, Sutherland, GR, Friend, K, Shaw, M, Corbett, M, Kim, HG, Geschwind, DH, Thomas, P, Haan, E, Ryan, S, McKee, S, Berkovic, SF, Futreal, PA, Stratton, MR, Mulley, JC & Gécz, J 2008, 'X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment', Nature Genetics, vol. 40, no. 6, pp. 776-781. https://doi.org/10.1038/ng.149

TY - JOUR

T1 - X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

AU - Dibbens, Leanne M.

AU - Tarpey, Patrick S.

AU - Hynes, Kim

AU - Bayly, Marta A.

AU - Scheffer, Ingrid E.

AU - Smith, Raffaella

AU - Bomar, Jamee

AU - Sutton, Edwina

AU - Vandeleur, Lucianne

AU - Shoubridge, Cheryl

AU - Edkins, Sarah

AU - Turner, Samantha J.

AU - Stevens, Claire

AU - O'Meara, Sarah

AU - Tofts, Calli

AU - Barthorpe, Syd

AU - Buck, Gemma

AU - Cole, Jennifer

AU - Halliday, Kelly

AU - Jones, David

AU - Lee, Rebecca

AU - Madison, Mark

AU - Mironenko, Tatiana

AU - Varian, Jennifer

AU - West, Sofie

AU - Widaa, Sara

AU - Wray, Paul

AU - Teague, John

AU - Dicks, Ed

AU - Butler, Adam

AU - Menzies, Andrew

AU - Jenkinson, Andrew

AU - Shepherd, Rebecca

AU - Gusella, James F.

AU - Afawi, Zaid

AU - Mazarib, Aziz

AU - Neufeld, Miriam Y.

AU - Kivity, Sara

AU - Lev, Dorit

AU - Lerman-Sagie, Tally

AU - Korczyn, Amos D.

AU - Derry, Christopher P.

AU - Sutherland, Grant R.

AU - Friend, Kathryn

AU - Shaw, Marie

AU - Corbett, Mark

AU - Kim, Hyung Goo

AU - Geschwind, Daniel H.

AU - Thomas, Paul

AU - Haan, Eric

AU - Ryan, Stephen

AU - McKee, Shane

AU - Berkovic, Samuel F.

AU - Futreal, P. Andrew

AU - Stratton, Michael R.

AU - Mulley, John C.

AU - Gécz, Jozef

N1 - Funding Information: We thank the members of the families studied for their participation and members of the International Genetics of Learning Disability (IGOLD) study for their collaboration. This work was supported by grants from the Australian National Health and Medical Research Council Program Grant 400121 (I.E.S., S.F.B., J.C.M. and J.G.), Thyne-Reid Charitable Trusts (L.M.D.) and the Wellcome Trust. We also acknowledge support to J.F.G. from US National Institutes of Health grant GM061354 and D.H.G. from US National Institute of Mental Health U.S. grant R01 MH 64547. We are grateful for access to the tissues used in these studies from the Developmental Brain and Tissue Bank at University of Maryland funded by the US National Institutes of Health (National Institute of Child Health and Human Development contracts NO1-HD-4-3368 and NO1-HD-4-3383).

PY - 2008/6

Y1 - 2008/6

N2 - Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

AB - Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

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X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

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