Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

被引：12

作者：

Deshwar, Ashish R. ^{[1
,2
]}

Cytrynbaum, Cheryl ^{[1
,2
]}

Murthy, Harsha ^{[2
]}

Zon, Jessica ^{[2
]}

Chitayat, David ^{[1
]}

Volpatti, Jonathan ^{[2
]}

Newbury-Ecob, Ruth ^{[3
]}

Ellard, Sian ^{[4
]}

Allen, Hana Lango ^{[5
]}

Yu, Emily P. ^{[6
]}

Noche, Ramil ^{[6
]}

Walker, Suzi ^{[7
]}

Scherer, Stephen W. ^{[7
]}

Mahida, Sonal ^{[8
]}

Elitt, Christopher M. ^{[9
,10
,11
]}

Nicolas, Gael ^{[12
,13
]}

Goldenberg, Alice ^{[12
,13
]}

Saugier-Veber, Pascale ^{[12
,13
]}

Lecoquierre, Francois ^{[12
,13
]}

Dabaj, Ivana ^{[14
,15
]}

Meddaugh, Hannah

Marble, Michael ^{[16
,17
]}

Keppler-Noreuil, Kim M. ^{[18
]}

Drayson, Lucy ^{[19
]}

Baranano, Kristin W. ^{[20
]}

Chassevent, Anna ^{[21
]}

Agre, Katie ^{[22
]}

Letard, Pascaline ^{[23
]}

Bilan, Frederic

Le Guyader, Gwenael ^{[24
]}

Laquerriere, Annie ^{[25
,26
]}

Ramsey, Keri ^{[27
]}

Henderson, Lindsay ^{[28
]}

Brady, Lauren ^{[29
]}

Tarnopolsky, Mark ^{[29
]}

Bainbridge, Matthew ^{[30
]}

Friedman, Jennifer ^{[30
,31
,32
]}

Capri, Yline ^{[33
]}

Athayde, Larissa ^{[34
]}

Kok, Fernando ^{[34
]}

Gurgel-Giannetti, Juliana ^{[35
]}

Ramos, Luiza L. P. ^{[34
]}

Blaser, Susan ^{[36
]}

Dowling, James J. ^{[2
,37
,38
]}

Weksberg, Rosanna ^{[1
,2
,38
,39
]}

机构：

[1] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G IX8, Canada

[2] Hosp Sick Children, Res Inst, Genet & Genome Biol, Toronto, ON M5G 0A4, Canada

[3] Univ Hosp Bristol NHS Fdn Trust, Dept Clin Genet, Bristol BS2 8EG, Avon, England

[4] Royal Devon & Exeter NHS Fdn Trust, Mol Genet, Exeter EX2 5DW, Devon, England

[5] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0SL, England

[6] Hosp Sick Children, Zebrafish Genet & Dis Models Core Facil, Toronto, ON M5G 0A4, Canada

[7] Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON M5G 0A4, Canada

[8] Boston Childrens Hosp, Dept Neurol, Epilepsy Genet Program, Boston, MA 02115 USA

[9] Boston Childrens Hosp, Dept Neurol, Fetal Neonatal Neurol Program, Boston, MA 02115 USA

[10] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA

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

[12] Normandie Univ, Dept Genet & Reference, Normandy Ctr Genom & Personalized Med, INSERM U1245,Ctr Dev Disorders,UNIROUEN, F-76000 Rouen, France

[13] Normandie Univ, Rouen Univ Hosp, F-76000 Rouen, France

[14] Normandie Univ, Rouen Univ Hosp, Dept Neonatol & Pediat Intens Care Pediat, UNIROUEN, F-76000 Rouen, France

[15] Normandie Univ, UNIROUEN, INSERM U1245, F-76000 Rouen, France

[16] Childrens Hosp New Orleans, Dept Genet, New Orleans, LA 70118 USA

[17] Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70112 USA

[18] Univ Wisconsin Madison, Dept Pediat, Madison, WI 53792 USA

[19] Pediat Specialists Virginia, Fairfax, VA 22031 USA

[20] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MA 21287 USA

[21] Kennedy Krieger Inst, Div Neurogenet, Baltimore, MA 21205 USA

[22] Mayo Clin, Dept Clin Genom, Rochester, NY 55905 USA

[23] CHU Poitiers, Serv Genet, Dept Clin Genet, CS 90577, F-86021 Poitiers, France

[24] Univ Poitiers, NEUVACOD EA3808, F-86073 Poitiers, France

[25] Normandie Univ, Normandy Ctr Genom & Personalized Med, Dept Pathol, UNIROUEN,INSERM U1245, F-76000 Rouen, France

[26] Rouen Univ Hosp, F-76000 Rouen, France

[27] Ctr Rare Childhood Disorders, Translat Genom Res Inst, Phoenix, AZ 85004 USA

[28] GeneDx, Gaithersburg, MD 20877 USA

[29] McMaster Univ, Dept Pediat, Hamilton, ON L8S 4K1, Canada

[30] Rady Childrens Inst Genom Med, San Diego, CA 92123 USA

[31] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA

[32] Univ Calif San Diego, Dept Pediat, San Diego, CA 92093 USA

[33] Hop Robert Debre, Assistance Publ Hop Paris AP HP, Dept Genet, F-75019 Paris, France

[34] Mendelics Genom Anal, BR-02511000 Sao Paulo, Brazil

[35] Univ Fed Minas Gerais, Dept Pediat, Sch Med, BR-31270901 Belo Horizonte, MG, Brazil

[36] Hosp Sick Children, Dept Diag Imaging, Toronto, ON M5G IX8, Canada

[37] Hosp Sick Children, Div Neurol, Toronto, ON M5G1X8, Canada

[38] Univ Toronto, Dept Mol Genet, Fac Med, Toronto, ON M5S IA8, Canada

[39] Univ Toronto, Inst Med Sci, Toronto, ON M5S IA8, Canada

来源：

BRAIN | 2022年 / 146卷 / 06期

关键词：

blood-brain barrier; CLDN5; brain calcifications;

D O I：

10.1093/brain/awac461

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.

引用

页码：2285 / 2297

页数：13

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