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Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly

Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly

Background: Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”. Methods: Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation. Results: We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi. Conclusions: This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

Cataract, Coatomer, COPB1, COPI, Intellectual disability, Microcephaly, Xenopus model, β-COP, beta-COP
1756-994X
Macken, William L.
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Godwin, Annie
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Wheway, Gabrielle
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Stals, Karen
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Nazlamova, Liliya
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Ellard, Sian
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Alfares, Ahmed
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Aloraini, Taghrid
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AlSubaie, Lamia
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Alfadhel, Majid
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Alajaji, Sulaiman
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Wai, Htoo A.
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Self, Jay
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Douglas, Andrew G.L.
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Kao, Alexander P.
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Guille, Matthew
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Baralle, Diana
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Macken, William L.
6ac04262-575f-45b7-bf3f-2dea561fd3a7
Godwin, Annie
90ba88ea-4a7c-44f4-bf70-9015c0d33194
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Stals, Karen
3636fac8-b1a2-4eae-be68-3d16d268a426
Nazlamova, Liliya
0cc21013-aeeb-4eef-af56-31f6fa0766fd
Ellard, Sian
6c9b0ede-8980-4602-b063-444b165baa09
Alfares, Ahmed
a0182507-03f5-47e1-a1f6-eaae4cd74b88
Aloraini, Taghrid
00f5c5d1-0165-4744-824b-64c356c32649
AlSubaie, Lamia
9561e70b-a451-4cea-af47-4b657d0740cf
Alfadhel, Majid
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Alajaji, Sulaiman
2eef03e9-e946-4ac3-8fdc-bcabe5d29483
Wai, Htoo A.
4428517b-33b3-42cb-9818-ca64763ab7bc
Self, Jay
0f6efc58-ae24-4667-b8d6-6fafa849e389
Douglas, Andrew G.L.
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Kao, Alexander P.
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Guille, Matthew
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Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91

Macken, William L., Godwin, Annie, Wheway, Gabrielle, Stals, Karen, Nazlamova, Liliya, Ellard, Sian, Alfares, Ahmed, Aloraini, Taghrid, AlSubaie, Lamia, Alfadhel, Majid, Alajaji, Sulaiman, Wai, Htoo A., Self, Jay, Douglas, Andrew G.L., Kao, Alexander P., Guille, Matthew and Baralle, Diana (2021) Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly. Genome Medicine, 13 (1), [34]. (doi:10.1186/s13073-021-00850-w).

Record type: Article

Abstract

Background: Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”. Methods: Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation. Results: We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi. Conclusions: This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

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More information

Accepted/In Press date: 11 February 2021
Published date: 25 February 2021
Additional Information: Funding Information: DB is generously supported by a National Institute of Health Research (NIHR) Research Professorship RP-2016-07-011. GW is supported by a Wellcome Trust Seed Award in Science 204378/Z/16/Z. We acknowledge support from the NIHR UK Rare Genetic Disease Research Consortium. The European Xenopus Reference Centre is supported by the Wellcome Trust (101480Z) and BBSRC (BB/K019988/1). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
Keywords: Cataract, Coatomer, COPB1, COPI, Intellectual disability, Microcephaly, Xenopus model, β-COP, beta-COP

Identifiers

Local EPrints ID: 449140
URI: http://eprints.soton.ac.uk/id/eprint/449140
ISSN: 1756-994X
PURE UUID: 3364556d-2851-4b9a-b84f-cada377d0fc7
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783
ORCID for Jay Self: ORCID iD orcid.org/0000-0002-1030-9963
ORCID for Andrew G.L. Douglas: ORCID iD orcid.org/0000-0001-5154-6714
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 18 May 2021 16:30
Last modified: 16 Sep 2021 01:58

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Contributors

Author: William L. Macken
Author: Annie Godwin
Author: Karen Stals
Author: Liliya Nazlamova
Author: Sian Ellard
Author: Ahmed Alfares
Author: Taghrid Aloraini
Author: Lamia AlSubaie
Author: Majid Alfadhel
Author: Sulaiman Alajaji
Author: Htoo A. Wai
Author: Jay Self ORCID iD
Author: Alexander P. Kao
Author: Matthew Guille
Author: Diana Baralle ORCID iD

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