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Biallelic variants on COPB1 cause a novel, severe intellectual disability syndrome with cataracts and varfiable microcephaly

Biallelic variants on COPB1 cause a novel, severe intellectual disability syndrome with cataracts and varfiable microcephaly
Biallelic variants on COPB1 cause a novel, severe intellectual disability syndrome with cataracts and varfiable 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.
1756-994X
34
Macken, William
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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
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Self, James
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Douglas, Andrew
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Kao, Alexander
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Guille, Matthew
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Baralle, Diana
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Macken, William
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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
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Self, James
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Douglas, Andrew
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Kao, Alexander
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Guille, Matthew
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Baralle, Diana
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Macken, William, Godwin, Annie, Wheway, Gabrielle, Stals, Karen, Nazlamova, Liliya, Ellard, Sian, Alfares, Ahmed, Aloraini, Taghrid, AlSubaie, Lamia, Alfadhel, Majid, Alajaji, Sulaiman, Wai, Htoo, Self, James, Douglas, Andrew, Kao, Alexander, Guille, Matthew and Baralle, Diana (2021) Biallelic variants on COPB1 cause a novel, severe intellectual disability syndrome with cataracts and varfiable 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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Accepted/In Press date: 10 February 2021
e-pub ahead of print date: 25 February 2021
Published date: 25 February 2021

Identifiers

Local EPrints ID: 447061
URI: http://eprints.soton.ac.uk/id/eprint/447061
ISSN: 1756-994X
PURE UUID: bdf12ce4-6a15-45f9-bdea-45ecb54368b6
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783
ORCID for James Self: ORCID iD orcid.org/0000-0002-1030-9963
ORCID for Andrew 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: 02 Mar 2021 17:32
Last modified: 04 Mar 2021 02:55

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Contributors

Author: William 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 Wai
Author: James Self ORCID iD
Author: Andrew Douglas ORCID iD
Author: Alexander Kao
Author: Matthew Guille
Author: Diana Baralle ORCID iD

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