Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly
Open Access
- 25 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Genome Medicine
- Vol. 13 (1), 1-19
- https://doi.org/10.1186/s13073-021-00850-w
Abstract
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”. 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. 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. 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.Keywords
Funding Information
- Wellcome Trust (101480Z, 101480Z, 204378/Z/16/Z)
- Biotechnology and Biological Sciences Research Council (BB/K019988/1, BB/K019988/1)
- Wellcome Trust (204378/Z/16/Z)
- National Institute for Health Research (RP-2016-07-011, RP-2016-07-011)
This publication has 61 references indexed in Scilit:
- Disruption of the Sec24d Gene Results in Early Embryonic Lethality in the MousePLOS ONE, 2013
- A Structure-Based Mechanism for Arf1-Dependent Recruitment of Coatomer to MembranesCell, 2012
- Coatomer and dimeric ADP ribosylation factor 1 promote distinct steps in membrane scissionThe Journal of cell biology, 2011
- The COPI vesicle complex binds and moves with survival motor neuron within axonsHuman Molecular Genetics, 2011
- Human Splicing Finder: an online bioinformatics tool to predict splicing signalsNucleic Acids Research, 2009
- Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi traffickingNature Genetics, 2006
- Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing SignalsJournal of Computational Biology, 2004
- Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humansProceedings of the National Academy of Sciences of the United States of America, 2002
- Improved Splice Site Detection in GenieJournal of Computational Biology, 1997
- 'Coatomer': a cytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesNature, 1991