Homozygous mutation in <i>murine retrovirus integration site 1</i> gene associated with a non‐syndromic form of isolated familial achalasia

Koehler, Katrin; Hmida, D.; Schlossmann, Jens; Landgraf, Dana; Reisch, Nicole; Schuelke, Markus; Huebner, Angela

doi:10.1111/nmo.13923

Cited by 2 publications

(2 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been proven that IRAG1 has an important role in the pathophysiological function of the gastrointestinal tract. MRVI1—the human homologue of IRAG1—exhibits a role in the development of achalasia, which can cause injuries of the mucous membrane [ 13 , 14 ]. Therefore, it is possible that a loss of IRAG1 results in gastrointestinal lesions or microbleeding because no duodenal ulcerations—as described in global Prkg1 mutants—were detected in Irag1 -deficient mice ( Figure S9 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Majer

Prueschenk

Schlossmann

2021

IJMS

Self Cite

View full text Add to dashboard Cite

Inositol 1,4,5triphosphate receptorassociated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMPdependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP3RI). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMPmediated IP3dependent Ca2+release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIβ to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1KO mice developed gastrointestinal bleeding, anemiaassociated splenomegaly and iron deficiency. Additionally, Irag1deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in the colon, spleen and stomach but did not change mRNAexpression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1deficient mice are possible in vivo model to investigate PKGIβ protein functions.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Majer

Prueschenk

Schlossmann

2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…This mutation resulted in a loss of the known interaction of IRAG1 and PKGIβ. As a consequence, the central role of IRAG1 in the regulation of Ca 2+ levels and the associated regulation of cGMP-regulated smooth muscle relaxation was lost [ 25 ]. This case report is consistent with previously reported data showing that microRNA (miRNA) regulates IRAG1 in esophageal SMCs in achalasia patients [ 26 ].…”

Section: Functional Features Of Irag1mentioning

confidence: 99%

Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2

Prüschenk

Majer

Schlossmann

2023

IJMS

Self Cite

View full text Add to dashboard Cite

The inositol triphosphate-associated proteins IRAG1 and IRAG2 are cGMP kinase substrate proteins that regulate intracellular Ca2+. Previously, IRAG1 was discovered as a 125 kDa membrane protein at the endoplasmic reticulum, which is associated with the intracellular Ca2+ channel IP3R-I and the PKGIβ and inhibits IP3R-I upon PKGIβ-mediated phosphorylation. IRAG2 is a 75 kDa membrane protein homolog of IRAG1 and was recently also determined as a PKGI substrate. Several (patho-)physiological functions of IRAG1 and IRAG2 were meanwhile elucidated in a variety of human and murine tissues, e.g., of IRAG1 in various smooth muscles, heart, platelets, and other blood cells, of IRAG2 in the pancreas, heart, platelets, and taste cells. Hence, lack of IRAG1 or IRAG2 leads to diverse phenotypes in these organs, e.g., smooth muscle and platelet disorders or secretory deficiency, respectively. This review aims to highlight the recent research regarding these two regulatory proteins to envision their molecular and (patho-)physiological tasks and to unravel their functional interplay as possible (patho-)physiological counterparts.

show abstract

Homozygous mutation in murine retrovirus integration site 1 gene associated with a non‐syndromic form of isolated familial achalasia

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 2 publications

References 35 publications

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2

Contact Info

Product

Resources

About