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Mutation of HERC2 causes developmental delay with Angelman-like features

Mutation of HERC2 causes developmental delay with Angelman-like features
Mutation of HERC2 causes developmental delay with Angelman-like features
Background: deregulation of the activity of the ubiquitin ligase E6AP (UBE3A) is well recognised to contribute to the development of Angelman syndrome (AS). The ubiquitin ligase HERC2, encoded by the HERC2 gene in patients with Angelman/Prader-Willi syndrome, is thought to be a key regulator of E6AP.

Methods and results: using a combination of autozygosity mapping and linkage analysis, we studied an autosomal-recessive neurodevelopmental disorder with some phenotypic similarities to AS, found among the Old Order Amish. Our molecular investigation identified a mutation in HERC2 associated with the disease phenotype. We establish that the encoded mutant HERC2 protein has a reduced half-life compared with its wild-type counterpart, which is associated with a significant reduction in HERC2 levels in affected individuals.

Conclusions: our data implicate a model in which disruption of HERC2 function relates to a reduction in E6AP activity resulting in neurodevelopmental delay, suggesting a previously unrecognised role of HERC2 in the pathogenesis of AS
0022-2593
65-73
Harlalka, Gaurav V.
1417f12a-ae2a-40ff-9a26-bf37e7dd9578
Baple, Emma L.
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Cross, Harold
548429f8-3bb7-4c9a-8543-7d2aff64b0a5
Kuhnle, Simone
3d374329-6bd1-48c9-9d25-2fcbf854e379
Cubillos-Rojas, Monica
d5ef1be1-6be3-45c7-9e78-3adb530435eb
Matentzoglu, Konstantin
ebdbf705-c0f9-46dd-9d12-4863a90fe5b2
Patton, Michael A.
6a9dcfa4-8434-4102-9b2b-6ab4d510a04d
Wagner, Karin
04be4849-ee1d-4eac-a6a8-ea7b74847d30
Coblentz, Roselyn
81be2933-c355-4014-b736-17bb044d9752
Ford, Debra L.
f870bc69-cd2a-4f74-a85e-49890f6e6438
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Chioza, Barry A.
edfb3b9a-5786-4490-a374-9a672060beb2
Scheffner, Martin
af280818-b3ac-4210-ba18-dad8df78e90a
Rosa, Jose Luis
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Crosby, Andrew H.
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Harlalka, Gaurav V.
1417f12a-ae2a-40ff-9a26-bf37e7dd9578
Baple, Emma L.
3069a362-2742-42a5-a7a7-e92a9af6fa88
Cross, Harold
548429f8-3bb7-4c9a-8543-7d2aff64b0a5
Kuhnle, Simone
3d374329-6bd1-48c9-9d25-2fcbf854e379
Cubillos-Rojas, Monica
d5ef1be1-6be3-45c7-9e78-3adb530435eb
Matentzoglu, Konstantin
ebdbf705-c0f9-46dd-9d12-4863a90fe5b2
Patton, Michael A.
6a9dcfa4-8434-4102-9b2b-6ab4d510a04d
Wagner, Karin
04be4849-ee1d-4eac-a6a8-ea7b74847d30
Coblentz, Roselyn
81be2933-c355-4014-b736-17bb044d9752
Ford, Debra L.
f870bc69-cd2a-4f74-a85e-49890f6e6438
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Chioza, Barry A.
edfb3b9a-5786-4490-a374-9a672060beb2
Scheffner, Martin
af280818-b3ac-4210-ba18-dad8df78e90a
Rosa, Jose Luis
553e43b0-d26d-4a3a-bad7-a93f2ba5cab1
Crosby, Andrew H.
241bc220-d13f-4d1c-8d2b-47ed6fa5cbbd

Harlalka, Gaurav V., Baple, Emma L., Cross, Harold, Kuhnle, Simone, Cubillos-Rojas, Monica, Matentzoglu, Konstantin, Patton, Michael A., Wagner, Karin, Coblentz, Roselyn, Ford, Debra L., Mackay, Deborah J.G., Chioza, Barry A., Scheffner, Martin, Rosa, Jose Luis and Crosby, Andrew H. (2013) Mutation of HERC2 causes developmental delay with Angelman-like features. Journal of Medical Genetics, 50 (2), 65-73. (doi:10.1136/jmedgenet-2012-101367). (PMID:23243086)

Record type: Article

Abstract

Background: deregulation of the activity of the ubiquitin ligase E6AP (UBE3A) is well recognised to contribute to the development of Angelman syndrome (AS). The ubiquitin ligase HERC2, encoded by the HERC2 gene in patients with Angelman/Prader-Willi syndrome, is thought to be a key regulator of E6AP.

Methods and results: using a combination of autozygosity mapping and linkage analysis, we studied an autosomal-recessive neurodevelopmental disorder with some phenotypic similarities to AS, found among the Old Order Amish. Our molecular investigation identified a mutation in HERC2 associated with the disease phenotype. We establish that the encoded mutant HERC2 protein has a reduced half-life compared with its wild-type counterpart, which is associated with a significant reduction in HERC2 levels in affected individuals.

Conclusions: our data implicate a model in which disruption of HERC2 function relates to a reduction in E6AP activity resulting in neurodevelopmental delay, suggesting a previously unrecognised role of HERC2 in the pathogenesis of AS

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More information

e-pub ahead of print date: 14 December 2012
Published date: February 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 346376
URI: http://eprints.soton.ac.uk/id/eprint/346376
ISSN: 0022-2593
PURE UUID: bc5aa4c3-e33e-4259-a9d6-0f6545bbc7f8
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 02 Jan 2013 09:18
Last modified: 10 Jan 2022 02:42

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Contributors

Author: Gaurav V. Harlalka
Author: Emma L. Baple
Author: Harold Cross
Author: Simone Kuhnle
Author: Monica Cubillos-Rojas
Author: Konstantin Matentzoglu
Author: Michael A. Patton
Author: Karin Wagner
Author: Roselyn Coblentz
Author: Debra L. Ford
Author: Barry A. Chioza
Author: Martin Scheffner
Author: Jose Luis Rosa
Author: Andrew H. Crosby

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