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dc.contributor.authorMacken, William L.
dc.contributor.authorGodwin, Annie
dc.contributor.authorWheway, Gabrielle
dc.contributor.authorStals, Karen
dc.contributor.authorNazlamova, Liliya
dc.contributor.authorEllard, Sian
dc.contributor.authorAlfares, Ahmed
dc.contributor.authorAloraini, Taghrid
dc.contributor.authorAlSubaie, Lamia
dc.contributor.authorAlfadhel, Majid
dc.contributor.authorAlajaji, Sulaiman
dc.contributor.authorWai, Htoo A.
dc.contributor.authorSelf, Jay
dc.contributor.authorDouglas, Andrew G. L.
dc.contributor.authorKao, Alexander P.
dc.contributor.authorGuille, Matthew
dc.contributor.authorBaralle, Diana
dc.identifier.citationMacken, W. L. et al. (2021) ‘Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly.’, Genome medicine, 13(1), p. 34. doi: 10.1186/s13073-021-00850-w.
dc.description.abstractBACKGROUND: 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 (?-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 ?-COP and ?'-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 ?-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.
dc.publisherBioMed Central
dc.rightsCopyright © The Author(s) 2021
dc.subjectIntellectual disability
dc.subjectXenopus model
dc.titleBiallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly.
dc.typeJournal Article
dc.identifier.journalGenome medicine
dc.description.noteThe article is available via Open Access. Click on the 'Additional link' above to access the full-text.
dc.description.admin-notePublished version, accepted version

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Copyright © The Author(s) 2021
Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2021