A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene

Abstract

PurposeWe sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.MethodsExome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed.ResultsWe identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes.ConclusionWe describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

The genetics of monogenic intestinal epithelial disorders

“…Many of these patients will likely require at least partial parenteral nutrition. Their clinical similarity to patients with cystic fibrosis has been noted in the literature, with Pseudomonas aeruginosa colonization and bronchiectasis at an early age (Bertoli-Avella et al 2021 ). Screening for pulmonary disease is, thus, an important clinical consideration in the care of these patients.…”

“…These patients were found to have causative homozygous mutations in the gene AGR2 ; thus, their clinical syndrome was named “Enteropathy caused by AGR2 deficiency, Goblet cell loss, and ER stress”, or EAGLES syndrome. Bertoli-Avella et al subsequently described a case series of 13 patients from 9 families and identified new causative variants in AGR2 (Bertoli-Avella et al 2021 ). Of the patients described in this study, 6 of the 13 from three separate families share an identical 8.2 Mb on chromosome 7 and are of Syrian descent.…”

“…The p.His117Tyr mutation falls between the thioredoxin-like domain and peptide-binding domain, which may alter the orientation of either of these domains or act by another mechanism. The p.Gly143Glu mutation falls shortly after the peptide-binding domain, and may alter result in interruption of a nearby alpha helix by the bulky glutamine side chain (Bertoli-Avella et al 2021 ). The identified splice-altering mutations in AGR2 , c.330 + 1G → T and c.330 + 1del, both involve the loss of normal exon 5 splicing.…”

Activation of goblet cell stress sensor IRE1β is controlled by the mucin chaperone AGR2

“…Finally, AGR2 has recently come into view as a disease-causing gene in a subset of patients displaying IBD-like symptoms, among others. A homozygous H117Y mutation was identified in twins with severe early-onset IBD 30 , and several other families have been identified that display profound inflammatory phenotypes at their mucosal surfaces due to mutations in AGR2 39 . As we have demonstrated that AGR2 H117Y loses the ability to interact with and block IRE1β, it is reasonable to assume that these patients do not only exhibit disturbed AGR2 chaperone function but may also be characterized by IRE1β hyperactivity (Fig 6).…”

“…The resolution of the nuclear magnetic resonance (NMR) structure of AGR2 revealed that AGR2 exists in a dimer, and that the single amino acid substitution mutations E60A and K64A behave as obligate monomers 38 . Recently, the amino acid substitution H117Y has been identified as disease-causing in families where homozygous individuals display severe early-onset inflammatory bowel disease (IBD) 30,39 . We wondered whether AGR2 requires dimerization and its thioredoxin motif to mediate the interaction with IRE1β.…”