Article Text
Abstract
The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1–4) and lobe B (COG5–8). The different functional roles of COG lobe A and lobe B might result in distinct clinical phenotypes in patients with COG-CDG (congenital disorders of glycosylation). This hypothesis is supported by three observations. First, knock-down of COG lobe A components affects Golgi morphology more severely than knock-down of COG lobe B components. Second, nearly all of the 27 patients with lobe B COG-CDG had bi-allelic truncating mutations, as compared with only one of the six patients with lobe A COG-CDG. This represents a frequency gap which suggests that bi-allelic truncating mutations in COG lobe A genes might be non-viable. Third, in support, large-scale exome data of healthy adults (Exome Aggregation Consortium (ExAC)) underline that COG lobe A genes are less tolerant to genetic variation than COG lobe B genes. Thus, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. In a larger perspective, clinical phenotypic severity corresponded nicely with tolerance to genetic variation. Therefore, genomic epidemiology can potentially be used as a photographic negative for mutational severity.
- COG
- conserved oligomeric Golgi complex
- CDG
- congenital disorder(s) of glycosylation
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Footnotes
Contributors HAH conceptualised and designed the study, collected the data, drafted the initial manuscript and approved the final manuscript as submitted. JJ and FF critically reviewed the initial manuscript and approved the final manuscript as submitted. PMvH conceptualised and supervised the design and data collection of the study, critically reviewed the initial manuscript and approved the final manuscript as submitted.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data are available on request.