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

被引：333

作者：

Dibbens, Leanne M. ^{[1
,2
]}

Tarpey, Patrick S. ^{[3
]}

Hynes, Kim ^{[1
,4
]}

Bayly, Marta A. ^{[1
]}

Scheffer, Ingrid E. ^{[5
,6
,7
]}

Smith, Raffaella ^{[3
]}

Bomar, Jamee ^{[8
,9
]}

Sutton, Edwina ^{[4
]}

Vandeleur, Lucianne ^{[1
]}

Shoubridge, Cheryl ^{[1
]}

Edkins, Sarah ^{[3
]}

Turner, Samantha J. ^{[5
,6
]}

Stevens, Claire ^{[3
]}

O'Meara, Sarah ^{[3
]}

Tofts, Calli ^{[3
]}

Barthorpe, Syd ^{[3
]}

Buck, Gemma ^{[3
]}

Cole, Jennifer ^{[3
]}

Halliday, Kelly ^{[3
]}

Jones, David ^{[3
]}

Lee, Rebecca ^{[3
]}

Madison, Mark ^{[3
]}

Mironenko, Tatiana ^{[3
]}

Varian, Jennifer ^{[3
]}

West, Sofie ^{[3
]}

Widaa, Sara ^{[3
]}

Wray, Paul ^{[3
]}

Teague, John ^{[3
]}

Dicks, Ed ^{[3
]}

Butler, Adam ^{[3
]}

Menzies, Andrew ^{[3
]}

Jenkinson, Andrew ^{[3
]}

Shepherd, Rebecca ^{[3
]}

Gusella, James F. ^{[10
,11
]}

Afawi, Zaid ^{[12
]}

Mazarib, Aziz ^{[12
]}

Neufeld, Miriam Y. ^{[12
]}

Kivity, Sara ^{[13
]}

Lev, Dorit ^{[14
]}

Lerman-Sagie, Tally ^{[14
]}

Korczyn, Amos D. ^{[10
,11
]}

Derry, Christopher P. ^{[5
,6
]}

Sutherland, Grant R. ^{[1
,2
,4
]}

Friend, Kathryn ^{[1
]}

Shaw, Marie ^{[1
]}

Corbett, Mark ^{[1
]}

Kim, Hyung-Goo ^{[10
,11
]}

Geschwind, Daniel H. ^{[8
,9
]}

Thomas, Paul ^{[4
]}

Haan, Eric ^{[1
,4
]}

机构：

[1] Womens & Childrens Hosp, Dept Med Genet, Adelaide, SA 5006, Australia

[2] Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA 5005, Australia

[3] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[4] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA 5005, Australia

[5] Univ Melbourne, Epilepsy Res Ctr, Heidelberg Repatriat Hosp, Heidelberg West, Vic 3081, Australia

[6] Univ Melbourne, Dept Med, Heidelberg Repatriat Hosp, Heidelberg West, Vic 3081, Australia

[7] Univ Melbourne, Dept Paediat, Royal Childrens Hosp, Parkville, Vic 3052, Australia

[8] Univ Calif Los Angeles, Program Neurogenet & Neurobehav Genet, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, Semel Inst Neurosci & Behav, David Geffen Sch Med, Los Angeles, CA 90095 USA

[10] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA

[11] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[12] Tel Aviv Sourasky Med Ctr, Dept Neurol, IL-64239 Tel Aviv, Israel

[13] Schneider Childrens Med Ctr, Dept Neurol, IL-49202 Petaq Tikvah, Israel

[14] Wolfson Med Ctr, Metab Neurogenet Clin, IL-58100 Holon, Israel

[15] AstraZeneca, Wilmington, DE 19803 USA

[16] Belfast City Hosp, No Ireland Reg Genet Serv, Belfast BT9 7AB, Antrim, North Ireland

来源：

NATURE GENETICS | 2008年 / 40卷 / 06期

基金：

英国惠康基金;

关键词：

D O I：

10.1038/ng.149

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：776 / 781

页数：6

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