X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.
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.
Dibbens
Leanne M
LM
Department of Genetic Medicine, Level 9 Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia. leanne.dibbens@cywhs.sa.gov.au
Tarpey
Patrick S
PS
Hynes
Kim
K
Bayly
Marta A
MA
Scheffer
Ingrid E
IE
Smith
Raffaella
R
Bomar
Jamee
J
Sutton
Edwina
E
Vandeleur
Lucianne
L
Shoubridge
Cheryl
C
Edkins
Sarah
S
Turner
Samantha J
SJ
Stevens
Claire
C
O'Meara
Sarah
S
Tofts
Calli
C
Barthorpe
Syd
S
Buck
Gemma
G
Cole
Jennifer
J
Halliday
Kelly
K
Jones
David
D
Lee
Rebecca
R
Madison
Mark
M
Mironenko
Tatiana
T
Varian
Jennifer
J
West
Sofie
S
Widaa
Sara
S
Wray
Paul
P
Teague
John
J
Dicks
Ed
E
Butler
Adam
A
Menzies
Andrew
A
Jenkinson
Andrew
A
Shepherd
Rebecca
R
Gusella
James F
JF
Afawi
Zaid
Z
Mazarib
Aziz
A
Neufeld
Miriam Y
MY
Kivity
Sara
S
Lev
Dorit
D
Lerman-Sagie
Tally
T
Korczyn
Amos D
AD
Derry
Christopher P
CP
Sutherland
Grant R
GR
Friend
Kathryn
K
Shaw
Marie
M
Corbett
Mark
M
Kim
Hyung-Goo
HG
Geschwind
Daniel H
DH
Thomas
Paul
P
Haan
Eric
E
Ryan
Stephen
S
McKee
Shane
S
Berkovic
Samuel F
SF
Futreal
P Andrew
PA
Stratton
Michael R
MR
Mulley
John C
JC
Gécz
Jozef
J
D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D041321:Chromosomes, Human, X; D018389:Codon, Nonsense / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D050172:Genes, X-Linked / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000473:pathology; D051379:Mice / Q000196:embryology; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000091363:Protocadherins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000378:metabolism
D015820:Cadherins; D018389:Codon, Nonsense; C438605:PCDH19 protein, human; D000091363:Protocadherins; D012333:RNA, Messenger