Genetics of Eosinophilic Esophagitis

Sherrill, Joseph D.; Blanchard, Carine

doi:10.1159/000357005

Cited by 9 publications

(10 citation statements)

References 76 publications

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“…A breakthrough came with the discovery that loss of function FLG mutations (R501X and 2282del4) are highly prevalent in the IV 28 and AD patients 29 ; this was replicated on different genetic backgrounds and ethnicities 24,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] , with hundreds of mutations now identi ed 46 . Importantly, while laggrin expression is almost entirely restricted to the epidermis, FLG mutations have been also shown to be linked to additional manifestations of atopic march and allergy, including food 47 and contact allergies 48 , asthma 49,50 , allergic rhinitis 49 and eosinophilic esophagitis 51 .…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

Paul

Szulc

Kobiela

et al. 2022

Preprint

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Background Loss of function mutation in FLG is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by FLG. Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin. Objective To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover. Methods The effect of proteasome inhibition on the expression of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed in silico using the DEGRONOPEDIA and Clustal Omega tool. Results Proteasome inhibition stabilizes profilaggrin and its high molecular weight derivatives. In silico analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. FLG mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes. Conclusions The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. FLG mutations alter those key elements, affecting the degradation routes and the mutated products’ stability.

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Section: Introductionmentioning

confidence: 99%

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

Paul

Szulc

Kobiela

et al. 2022

Preprint

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“…Eosinophilic esophagitis (EoE) is a complex genetic disorder characterized by eosinophilic inflammation within the esophagus [ 1 ]. It is defined by symptoms of esophageal dysfunction such as emesis, dysphagia, or feeding difficulties, in patients with an esophageal biopsy demonstrating at least 15 eosinophils/high power field, in the absence of other conditions associated with esophageal eosinophilia such as gastroesophageal reflux disease or achalasia [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…EoE is most frequently seen in Caucasian males and individuals of European ancestry, highlighting a genetic etiology of the disease. EoE has often been observed to occur in multiple family members, particularly siblings, in a non-Mendelian pattern, indicating that the hereditary component of EoE is likely complex and multifactorial in nature [ 1 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

A Case of Two Brothers With Dysphagia Due to Eosinophilic Esophagitis

Gil¹,

Cross²,

Gil³

2022

Cureus

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Eosinophilic esophagitis (EoE) is a disease that is still not fully understood. Its pathogenesis, while increasingly clarified, still remains highly complex, which means that no curative treatment has been defined for this clinical entity. It is clear that it is a disease of multifactorial etiology, in which both genetics and environmental factors, especially those related to childhood, have considerable weight, and there is an important allergenic factor as well. We present the case of two brothers with EoE. Two male patients aged 20 and 22 years, white, with a personal history of atopy, allergic rhinitis, and dermatitis, consulted the gastroenterologist for dysphagia. Endoscopy and esophageal biopsy showed elements compatible with EoE in both of them. Treatment was conducted with proton pump inhibitor (PPI) monotherapy in one of the brothers, and PPI with oral steroid in the other, both of which led to good results in terms of symptoms. In the first case, histologic evidence of the disease persisted despite the symptomatic resolution; the second did not pursue a follow-up. The biggest questions pertaining to the treatment of this condition are as follows: Is suppression of gastric acidity enough? Should we use steroids? How about a combination of both? Should we adopt new therapies? New studies involving randomized trials should be conducted to address these questions in order to treat each patient individually with an effective and practical approach that is also supported by the literature.

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“…(1–12) Although these studies have greatly enhanced our understanding of this increasingly common disease,(13, 14) our understanding of etiologic risk factors for disease remains elusive. Studies of genetics have identified several susceptibility loci for disease development,(15–18) and these are described elsewhere in this issue, but recent family studies suggest that relatively little of the disease can be explained by heritability alone. (19) This, together with the rapidly increasing incidence of disease that is not entirely explained by increased diagnostic awareness or volume of upper endoscopy procedures,(9, 12, 20) suggests that environmental factors not only contribute, but likely play a large role in EoE etiology.…”

Section: Introductionmentioning

confidence: 99%

Environmental and infectious factors in eosinophilic esophagitis

Jensen

Dellon

2015

Best Practice & Research Clinical Gastroenterology

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Identifying possible environmental or infectious etiologic factors for eosinophilic esophagitis (EoE) may offer insight into opportunities for disease prevention and treatment. We reviewed the current literature to assess environmental and infectious factors evaluated in EoE. Few studies have been conducted, however a consistent inverse association between EoE and H. pylori has been described. Several studies suggest a weak association between season and EoE diagnosis, but the evidence is inconclusive. EoE has also been associated with early life factors, including Cesarean delivery and antibiotic use. Larger studies are needed to evaluate these associations more thoroughly. Several papers have speculated the potential for anti-secretory agents to contribute to EoE. This has not been formerly evaluated. In summary, there is significant opportunity in the future to advance our understanding of possible environmental etiologic factors for EoE.

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Genetics of Eosinophilic Esophagitis

Cited by 9 publications

References 76 publications

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

A Case of Two Brothers With Dysphagia Due to Eosinophilic Esophagitis

Environmental and infectious factors in eosinophilic esophagitis

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