Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy

Daniel T. Pederick, Kay L. Richards, Sandra G. Piltz, Raman Kumar, Stefka Mincheva-Tasheva, Simone A. Mandelstam, Russell C. Dale, Ingrid E. Scheffer, Jozef Gecz, Steven Petrou, James N. Hughes, Paul Q. Thomas

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy. Pederick et al. report a cellular mechanism explaining the unique X-linked inheritance pattern of PCDH19 epilepsy. PCDH19 specifies binding affinities such that mosaic expression in females leads to striking segregation of WT and null cortical progenitors and abnormal network activity.

LanguageEnglish
Pages59-66.e5
JournalNeuron
Volume97
Issue number1
DOIs
Publication statusPublished - 3 Jan 2018

Keywords

  • PCDH19-GCE
  • adhesion molecules
  • cell sorting
  • cell-cell adhesion code
  • cortical development
  • epilepsy
  • protocadherin 19
  • protocadherins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Pederick, D. T., Richards, K. L., Piltz, S. G., Kumar, R., Mincheva-Tasheva, S., Mandelstam, S. A., ... Thomas, P. Q. (2018). Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy. Neuron, 97(1), 59-66.e5. https://doi.org/10.1016/j.neuron.2017.12.005
Pederick, Daniel T. ; Richards, Kay L. ; Piltz, Sandra G. ; Kumar, Raman ; Mincheva-Tasheva, Stefka ; Mandelstam, Simone A. ; Dale, Russell C. ; Scheffer, Ingrid E. ; Gecz, Jozef ; Petrou, Steven ; Hughes, James N. ; Thomas, Paul Q. / Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy. In: Neuron. 2018 ; Vol. 97, No. 1. pp. 59-66.e5.
@article{3df602274ed5455eb670eabad6af3fa1,
title = "Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy",
abstract = "X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy. Pederick et al. report a cellular mechanism explaining the unique X-linked inheritance pattern of PCDH19 epilepsy. PCDH19 specifies binding affinities such that mosaic expression in females leads to striking segregation of WT and null cortical progenitors and abnormal network activity.",
keywords = "PCDH19-GCE, adhesion molecules, cell sorting, cell-cell adhesion code, cortical development, epilepsy, protocadherin 19, protocadherins",
author = "Pederick, {Daniel T.} and Richards, {Kay L.} and Piltz, {Sandra G.} and Raman Kumar and Stefka Mincheva-Tasheva and Mandelstam, {Simone A.} and Dale, {Russell C.} and Scheffer, {Ingrid E.} and Jozef Gecz and Steven Petrou and Hughes, {James N.} and Thomas, {Paul Q.}",
year = "2018",
month = "1",
day = "3",
doi = "10.1016/j.neuron.2017.12.005",
language = "English",
volume = "97",
pages = "59--66.e5",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",

}

Pederick, DT, Richards, KL, Piltz, SG, Kumar, R, Mincheva-Tasheva, S, Mandelstam, SA, Dale, RC, Scheffer, IE, Gecz, J, Petrou, S, Hughes, JN & Thomas, PQ 2018, 'Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy', Neuron, vol. 97, no. 1, pp. 59-66.e5. https://doi.org/10.1016/j.neuron.2017.12.005

Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy. / Pederick, Daniel T.; Richards, Kay L.; Piltz, Sandra G.; Kumar, Raman; Mincheva-Tasheva, Stefka; Mandelstam, Simone A.; Dale, Russell C.; Scheffer, Ingrid E.; Gecz, Jozef; Petrou, Steven; Hughes, James N.; Thomas, Paul Q.

In: Neuron, Vol. 97, No. 1, 03.01.2018, p. 59-66.e5.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy

AU - Pederick, Daniel T.

AU - Richards, Kay L.

AU - Piltz, Sandra G.

AU - Kumar, Raman

AU - Mincheva-Tasheva, Stefka

AU - Mandelstam, Simone A.

AU - Dale, Russell C.

AU - Scheffer, Ingrid E.

AU - Gecz, Jozef

AU - Petrou, Steven

AU - Hughes, James N.

AU - Thomas, Paul Q.

PY - 2018/1/3

Y1 - 2018/1/3

N2 - X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy. Pederick et al. report a cellular mechanism explaining the unique X-linked inheritance pattern of PCDH19 epilepsy. PCDH19 specifies binding affinities such that mosaic expression in females leads to striking segregation of WT and null cortical progenitors and abnormal network activity.

AB - X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy. Pederick et al. report a cellular mechanism explaining the unique X-linked inheritance pattern of PCDH19 epilepsy. PCDH19 specifies binding affinities such that mosaic expression in females leads to striking segregation of WT and null cortical progenitors and abnormal network activity.

KW - PCDH19-GCE

KW - adhesion molecules

KW - cell sorting

KW - cell-cell adhesion code

KW - cortical development

KW - epilepsy

KW - protocadherin 19

KW - protocadherins

UR - http://www.scopus.com/inward/record.url?scp=85040576865&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2017.12.005

DO - 10.1016/j.neuron.2017.12.005

M3 - Article

VL - 97

SP - 59-66.e5

JO - Neuron

T2 - Neuron

JF - Neuron

SN - 0896-6273

IS - 1

ER -

Pederick DT, Richards KL, Piltz SG, Kumar R, Mincheva-Tasheva S, Mandelstam SA et al. Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy. Neuron. 2018 Jan 3;97(1):59-66.e5. https://doi.org/10.1016/j.neuron.2017.12.005