Mutations in the X-linked <i>ATP6AP2</i> cause a glycosylation disorder with autophagic defects

Rujano, Maria A.; Serio, M; Panasyuk, Ganna; Péanne, Romain; Reunert, Janine; Rymen, Daisy; Hauser, Virginie; Park, Julien H.; Freisinger, Peter; Souche, Erika; Guida, Maria Clara; Maier, Esther M.; Wada, Yoshinao; Jäger, Stefanie; Krogan, Nevan J.; Kretz, Oliver; Nobre, Susana; Garcia, Paula; Quelhas, Dulce; Bird, Thomas D.; Raskind, Wendy H.; Schwake, Michael; Duvet, Sandrine; Foulquier, François; Matthijs, Gert; Marquardt, Thorsten; Simons, Matias

doi:10.1084/jem.20170453

Cited by 69 publications

(84 citation statements)

References 65 publications

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“…The patients experienced recurrent infections (eg, localized respiratory tract infections, peritonitis and sepsis). Immunological investigations showed decreased Ig counts (restricted to IgG deficiency in one patient) and altered T cell counts (low levels of CD4 + and increased levels of CD8 + lymphocytes) . Remarkably, in a mouse model of Atp6ap2 deficiency, leukocyte depletion with pronounced lymphopenia and increased TNFα production were reported.…”

Section: The Immunological Impact Of Glycosylation Defects—an Update mentioning

confidence: 93%

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CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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Glycosylation is an essential biological process that adds structural and functional diversity to cells and molecules, participating in physiological processes such as immunity. The immune response is driven and modulated by protein‐attached glycans that mediate cell‐cell interactions, pathogen recognition and cell activation. Therefore, abnormal glycosylation can be associated with deranged immune responses. Within human diseases presenting immunological defects are congenital disorders of glycosylation (CDG), a family of around 130 rare and complex genetic diseases. In this review, we have identified 23 CDG with immunological involvement, characterized by an increased propensity to—often life‐threatening—infection. Inflammatory and autoimmune complications were found in 7 CDG types. CDG natural history(ies) and the mechanisms behind the immunological anomalies are still poorly understood. However, in some cases, alterations in pathogen recognition and intracellular signaling (eg, TGF‐β1, NFAT, and NF‐κB) have been suggested. Targeted therapies to restore immune defects are only available for PGM3‐CDG and SLC35C1‐CDG. Fostering research on glycoimmunology may elucidate the involved pathophysiological mechanisms and open new therapeutic avenues, thus improving CDG patients' quality of life.

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Section: The Immunological Impact Of Glycosylation Defects—an Update mentioning

confidence: 93%

“…Regarding infection treatment, intravenous (IV) Ig administration has resulted in clinical improvement in many CDG patients . Nevertheless, patients with hypogammaglobulinemia refractive to Ig therapy have been reported .…”

Section: Immunomodulatory Therapeutic Avenues In Cdgmentioning

confidence: 99%

CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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“…Mutations in the ATP6AP2 gene were associated with disorders of glycosylation and autophagy in a small group of patients. 101,102 Elevated plasma sPRR levels were described in several studies of gestational diabetes mellitus, 69,103,104 yet plasma sPRR levels in diabetic patients were similar to those in healthy control subjects. 76 Ongoing research on the tissue-specific role of the PRR in glucose and lipid metabolism will help clarify these conflicting results and determine if the PRR is a reasonable therapeutic target.…”

Section: Role Of the (Pro)renin Receptor In Glucose And Lipid Metabolismmentioning

confidence: 94%

“…Similarly, a recent study described an association between missense mutations in the extracellular domain of the PRR with a "congenital glycosylation disorder" manifested by liver disease, immunodeficiency, and psychomotor impairment in humans. 101 The authors studied this phenomenon in a mouse model with liver-specific knockdown of PRR and proposed that the clinical symptoms of the glycosylation disorder were likely a result of impaired vacuolar H þ -ATPase assembly, leading to defects in autophagy. 101 Taken together, these studies highlight a novel role of the PRR in lipid metabolism and liver function.…”

Section: Role Of the (Pro)renin Receptor In Glucose And Lipid Metabolismmentioning

confidence: 99%

“…101 The authors studied this phenomenon in a mouse model with liver-specific knockdown of PRR and proposed that the clinical symptoms of the glycosylation disorder were likely a result of impaired vacuolar H þ -ATPase assembly, leading to defects in autophagy. 101 Taken together, these studies highlight a novel role of the PRR in lipid metabolism and liver function.…”

Section: Role Of the (Pro)renin Receptor In Glucose And Lipid Metabolismmentioning

confidence: 99%

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The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

Ramkumar

Kohan

2019

Kidney International

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The (pro)renin receptor (PRR) is a multifunctional protein that is expressed in multiple organs. Binding of prorenin/ renin to the PRR activates angiotensin II-dependent and angiotensin II-independent pathways. The PRR is also involved in autophagy and Wnt/ß catenin signaling, functions that are not contingent on prorenin binding. Emerging evidence suggests that the PRR plays an important role in blood pressure regulation and glucose and lipid metabolism. Herein, we review PRR function in health and disease, with particular emphasis on hypertension and the metabolic syndrome.

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Mutations in the V‐ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease

et al. 2020

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BaCKgRoUND aND aIMS: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy. appRoaCH aND ReSUltS: Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways. CoNClUSIoNS: Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.

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Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

Abstract: Rujano et al. report mutations in ATP6AP2 leading to liver disease, immunodeficiency, and psychomotor impairment. ATP6AP2 deficiency impairs the assembly and function of the V-ATPase proton pump, causing defects in protein glycosylation and autophagy.

Cited by 69 publications

References 65 publications

CDG and immune response: From bedside to bench and back

CDG and immune response: From bedside to bench and back

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

Mutations in the V‐ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease

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