N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity

Tambe, Mitali A.; Ng, Bobby G.; Freeze, Hudson H.

doi:10.1016/j.celrep.2019.11.097

Cited by 41 publications

(45 citation statements)

References 59 publications

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“…intermediary protein that in turn, regulates NKCC1. This was recently found to be the case for 10 aquaporins in NGLY1 deficient cells (Tambe, Ng, & Freeze, 2019). NGLY1 was found to regulate 11 the abundance of transcription factors Atf1/Creb1 which then regulate the transcription of several 12 aquaporin subunits.…”

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confidence: 85%

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ADrosophilanatural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

Talsness

Owings

Coelho

et al. 2020

Preprint

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15N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in 16the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, 17seizures, and a lack of sweat and tears. To model the phenotypic variability observed among 18 patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse 19 strains. The resulting progeny showed a phenotypic spectrum from 0-100% lethality. Association 20analysis on the lethality phenotype as well as an evolutionary rate covariation analysis generated 21lists of modifying genes, providing insight into NGLY1 function and disease. The top association 22hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1 -/-mouse 23 cells demonstrated that NKCC1 is misglycosylated and has reduced function, making it only the 24 second confirmed NGLY1 enzymatic substrate. The misregulation of this ion transporter may 25 explain the observed defects in secretory epithelium function in NGLY1 deficiency patients. 26

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confidence: 85%

“…two distinctly different manners: regulating abundance through transcription factor intermediaries 17 (Tambe et al, 2019), and regulating activity through deglycosylation and conversion of 18 asparagine residues to aspartic acids (Lehrbach et al, 2019). While the exact method of NGLY1 19…”

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confidence: 99%

ADrosophilanatural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

Talsness

Owings

Coelho

et al. 2020

Preprint

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“…Nfe2l1 -/-MEFs were obtained from Dr. Senthil Radhakrishnan and were verified based on impaired proteasome bounce-back response [28]. Human fibroblasts derived from a healthy 5-year old male control (GM05381) was from Coriell Institute for Medical Research (Camden, NJ) and were kindly provided by Dr. Hud Freeze [45]. The patients and parent fibroblasts had the following genotypes: Parent #1, NGLY1 R401X/+ ; parent #2, NGLY1 R458fs/+ ; patient #1, NGLY1 R401X/…”

Section: Cell Culture and Drug Treatmentmentioning

confidence: 99%

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

et al. 2020

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Mutations in human N-glycanase 1 (NGLY1) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as NGLY1 deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called "nuclear factor erythroid 2-like 1" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its in vivo consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the Drosophila larval intestine results in a severe reduction in the level of AMP-activated protein kinase α (AMPKα), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality. Ngly1–/– mouse embryonic fibroblasts and NGLY1 deficiency patient fibroblasts also show reduced AMPKα levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPKα level and impaired energy metabolism observed in NGLY1 deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in NGLY1 deficiency and suggest AMPK signaling as a therapeutic target in this disease.

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“…Aquaporins play a major role in tear secretion and brain functions. The decrease of aquaporin expression may underlie the hypolacrimia/alacrimia and neurological disturbances observed in NGLY1 deficiency ( Figure 1A) [16]. These numerous roles of NGLY1 are certainly at the origin of the multisystemic involvement in this complex disease.…”

Section: Introductionmentioning

confidence: 99%

NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation

Dabaj

Sudrié-Arnaud

Lecoquierre

et al. 2021

Life

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NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay—hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima.

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N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity

Cited by 41 publications

References 59 publications

ADrosophilanatural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

ADrosophilanatural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation

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