Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly
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”. Metho...
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2021-02-01
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Series: | Genome Medicine |
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Online Access: | https://doi.org/10.1186/s13073-021-00850-w |
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doaj-80c8d687a6984db2bccd3da2c3505ebc |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
William L. Macken Annie Godwin Gabrielle Wheway Karen Stals Liliya Nazlamova Sian Ellard Ahmed Alfares Taghrid Aloraini Lamia AlSubaie Majid Alfadhel Sulaiman Alajaji Htoo A. Wai Jay Self Andrew G. L. Douglas Alexander P. Kao Matthew Guille Diana Baralle |
spellingShingle |
William L. Macken Annie Godwin Gabrielle Wheway Karen Stals Liliya Nazlamova Sian Ellard Ahmed Alfares Taghrid Aloraini Lamia AlSubaie Majid Alfadhel Sulaiman Alajaji Htoo A. Wai Jay Self Andrew G. L. Douglas Alexander P. Kao Matthew Guille Diana Baralle Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly Genome Medicine COPB1 COPI β-COP Microcephaly Cataract Xenopus model |
author_facet |
William L. Macken Annie Godwin Gabrielle Wheway Karen Stals Liliya Nazlamova Sian Ellard Ahmed Alfares Taghrid Aloraini Lamia AlSubaie Majid Alfadhel Sulaiman Alajaji Htoo A. Wai Jay Self Andrew G. L. Douglas Alexander P. Kao Matthew Guille Diana Baralle |
author_sort |
William L. Macken |
title |
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly |
title_short |
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly |
title_full |
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly |
title_fullStr |
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly |
title_full_unstemmed |
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly |
title_sort |
biallelic variants in copb1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2021-02-01 |
description |
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. |
topic |
COPB1 COPI β-COP Microcephaly Cataract Xenopus model |
url |
https://doi.org/10.1186/s13073-021-00850-w |
work_keys_str_mv |
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doaj-80c8d687a6984db2bccd3da2c3505ebc2021-03-11T11:26:47ZengBMCGenome Medicine1756-994X2021-02-0113111910.1186/s13073-021-00850-wBiallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephalyWilliam L. Macken0Annie Godwin1Gabrielle Wheway2Karen Stals3Liliya Nazlamova4Sian Ellard5Ahmed Alfares6Taghrid Aloraini7Lamia AlSubaie8Majid Alfadhel9Sulaiman Alajaji10Htoo A. Wai11Jay Self12Andrew G. L. Douglas13Alexander P. Kao14Matthew Guille15Diana Baralle16Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation TrustEuropean Xenopus Resource Centre, University of Portsmouth School of Biological SciencesFaculty of Medicine, University of Southampton, Duthie Building, Southampton General HospitalExeter Genomics Laboratory, Level 3 RILD building, Royal Devon & Exeter NHS Foundation TrustFaculty of Medicine, University of Southampton, Duthie Building, Southampton General HospitalExeter Genomics Laboratory, Level 3 RILD building, Royal Devon & Exeter NHS Foundation TrustDepartment of Pediatrics, College of Medicine, Qassim UniversityDepartment of Pathology and Laboratory Medicine, King Abdulaziz Medical CityDivision of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA)Faculty of Medicine, University of Southampton, Duthie Building, Southampton General HospitalFaculty of Medicine, University of Southampton, Duthie Building, Southampton General HospitalWessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation TrustZeiss Global Centre, School of Mechanical and Design Engineering, University of PortsmouthEuropean Xenopus Resource Centre, University of Portsmouth School of Biological SciencesWessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation TrustAbstract 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.https://doi.org/10.1186/s13073-021-00850-wCOPB1COPIβ-COPMicrocephalyCataractXenopus model |