This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g. "cytosolic_deglycosylation#Cytosolic Glycan Catabolite Dysregulation").
Key conformance target: the central_effector node "Cytosolic Glycan Catabolite Dysregulation" - the one lesion both known CDDG genes converge on regardless of which enzyme is lost, and named for the catabolite pool rather than for free oligosaccharides alone so that both arms can attach honestly. Conforming entries substitute the disorder-specific enzyme (NGLY1 peptide:N-glycanase, MAN2C1 cytosolic alpha-mannosidase) and, where the arm applies, route through the enzyme-specific upstream node: "Impaired Cytosolic Deglycosylation of Retrotranslocated Glycoproteins" for NGLY1, which is a claim about ERAD substrate handling that a MAN2C1 conformer must not make.
"Loss of Deglycosylation-Dependent Substrate Activation" is deliberately an NGLY1-only branch and is NOT part of the shared chain. It captures the sequence-editing function - Asn-to-Asp conversion of NFE2L1/Nrf1 - which has no MAN2C1 counterpart, since trimming a released oligosaccharide edits no protein. A conformer should attach here only with direct evidence of a deglycosylation-dependent activation step, not on the strength of a proteasome or oxidative-stress phenotype alone, which many unrelated disorders produce.
Boundary. This module is the deliberate complement of congenital_disorder_of_glycosylation, which models failure of N-glycan synthesis and attachment; nothing conforms to both for the same node. It is also distinct from lysosomal_substrate_accumulation - that module's substrate builds up inside the lysosome behind a deficient acid hydrolase, whereas the free oligosaccharides here accumulate in the cytosol and the pathway is explicitly non-lysosomal glycan degradation. It is not loss_of_proteostasis either: the ERAD and proteasome involvement in the NGLY1 arm is a specific enzymatic step and a specific transcriptional response, not a generalized collapse of degradative capacity.
Modules bind GO and CL terms only and do not use CHEBI or gene bindings; the free oligosaccharide is therefore described in prose rather than bound to a CHEBI class. This is not an Xogenesis module - nothing pathological is formed, a normal catabolic route fails.
ENGASE is the module's built-in therapeutic hypothesis and its clearest open question. Cytoplasmic endo-beta-N-acetylglucosaminidase is a second de-N-glycosylating enzyme that leaves a single GlcNAc on the asparagine, and deleting it partially rescues the embryonic lethality of Ngly1-null mice. Whether an ENGASE inhibitor would help a human patient is untested, and the rescue is recorded here as a mechanistic finding rather than as a treatment.
Is the dysregulated cytosolic free-oligosaccharide pool itself pathogenic, or is it a marker of the disposal route that is actually failing?
KNOWLEDGE GAP
OPEN
gap_cddg_free_oligosaccharide_toxicity
Attached to:
Cytosolic Glycan Catabolite Dysregulation
Neurodevelopmental and Multisystem Dysfunction
The module's central effector is the one lesion both CDDG genes share, and it is measurable in patient cells, which is why it is the conformance target. It is not thereby shown to be toxic. No dose-response between free-oligosaccharide burden and clinical severity has been reported in either disorder, the measurements are made in fibroblasts and haploid-cell-line models rather than in the neural tissue where the phenotype falls, and the edge from this node to the clinical consequence is typed INDIRECT_UNKNOWN_INTERMEDIATES in both conformers for that reason. The alternative reading - that the pool is an accessible readout of a failing route whose real damage lies elsewhere, for instance in undeglycosylated ERAD substrates or in unactivated Nrf1 - is equally consistent with everything published.
Proposed experiments:
Free-oligosaccharide burden against clinical severity across both CDDG genes
Manipulate the pool without restoring the enzyme
Would inhibiting ENGASE benefit human NGLY1 deficiency, as deleting it benefits Ngly1-null mice?
HUMAN MODEL MISMATCH
OPEN
gap_cddg_engase_inhibition_therapeutic
Attached to:
Impaired Cytosolic Deglycosylation of Retrotranslocated Glycoproteins
Deleting Engase partially rescues the embryonic lethality of Ngly1-null mice on a C57BL/6 background and strongly suppresses the phenotype of viable mixed-background animals, which is the strongest genetic evidence anywhere in this module about what the damaging event actually is. The translational gap is real in both directions. Human NGLY1 deficiency is not embryonically lethal, so the phenotype being rescued in mouse is not the phenotype a patient has; genetic background alone partially rescues the mouse lethality, which means the rescue is measured against a strain-specific severity that has no human analogue; and germline deletion from conception is not the same intervention as pharmacological inhibition started after diagnosis. No ENGASE inhibitor has been tested in a patient.
Proposed experiments:
Postnatal ENGASE inhibition in a viable Ngly1-deficient rodent
ENGASE-dependent substrate signature in patient cells
Cytosolic Deglycosylation Enzyme Deficiency
trigger
Biallelic loss-of-function variants abolish or markedly reduce one of the cytosolic enzymes that dispose of already-synthesized glycans: peptide:N-glycanase, which hydrolyses the glycan-asparagine bond on retrotranslocated glycoproteins, or cytosolic alpha-mannosidase, which trims the resulting free oligosaccharides. Conforming disorder nodes substitute the specific enzyme and its molecular function.
Downstream
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Impaired Cytosolic Deglycosylation of Retrotranslocated Glycoproteins
The peptide:N-glycanase arm. Loss of the amidase leaves N-glycans attached to glycoproteins that have already been pulled out of the ER for degradation.
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Cytosolic Glycan Catabolite Dysregulation
Both arms reach the shared lesion: the cytosolic alpha-mannosidase arm directly, by failing to trim free oligosaccharides, and the peptide:N-glycanase arm by changing which species enter the pool and by what route.
Show evidence (2 references)
"The cytosolic peptide:N-glycanase (PNGase, NGLY1 in mammals) is an enzyme that removes N-glycans from misfolded glycoproteins."
Defines the peptide:N-glycanase arm of the enzyme deficiency this trigger node represents.
"The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1"
Defines the cytosolic alpha-mannosidase arm of the same trigger node.
Impaired Cytosolic Deglycosylation of Retrotranslocated Glycoproteins
amplifier
The peptide:N-glycanase-specific arm. Misfolded N-linked glycoproteins are retrotranslocated from the ER into the cytosol for proteasomal degradation, and normally lose their bulky N-glycan first. Without that step the ERAD route is perturbed, and a second cytosolic de-N-glycosylating enzyme, ENGASE, acts on the same substrates instead, leaving a single GlcNAc on the asparagine. A MAN2C1-type conformer must not attach here - it makes a claim about glycoprotein substrate handling, not about free-oligosaccharide trimming.
Downstream
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Loss of Deglycosylation-Dependent Substrate Activation
A subset of peptide:N-glycanase substrates are not being disposed of but edited: deglycosylation converts glycosylated asparagine to aspartate and thereby activates them.
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Cytosolic Glycan Catabolite Dysregulation
Glycans released from ERAD substrates are a principal source of the cytosolic free-oligosaccharide pool, so a block at this step changes both the flux into the pool and the species it contains.
Show evidence (2 references)
"The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome."
Places the deglycosylation step inside the ERAD-proteasome route this node represents.
"the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice"
Establishes the competing ENGASE route on the same substrates, and that removing it is protective - the genetic evidence that the damage is done by what happens to undeglycosylated substrates, not merely by their persistence.
Cytosolic Glycan Catabolite Dysregulation
central effector
The rate-limiting, disorder-agnostic node and the key conformance target: the products of cytosolic, non-lysosomal glycan degradation are wrong - accumulating, processed too slowly, or of the wrong species. The two arms reach it with different catabolites, which conforming entries substitute. Loss of cytosolic alpha-mannosidase leaves free oligosaccharides unprocessed and accumulating. Loss of peptide:N-glycanase diverts glycoprotein disposal down the ENGase route and leaves GlcNAc-asparagine (GNA) accumulating instead, measurable in patient plasma, urine, and dried blood spots. Naming the node for the catabolite pool rather than for free oligosaccharides specifically is deliberate: a conformer should not have to claim free-oligosaccharide accumulation to attach here when its evidenced catabolite is a glycoasparagine.
Downstream
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Neurodevelopmental and Multisystem Dysfunction
The link from the cytosolic biochemical lesion to the clinical phenotype is asserted from co-occurrence in the same patients, not demonstrated. Conforming entries should preserve the weak causal typing rather than upgrading it.
Show evidence (2 references)
"MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells."
The defining measurement of this node, made in patient-derived cells.
"We identified aspartylglycosamine as the only significantly increased compound"
The peptide:N-glycanase arm's counterpart measurement: an accumulating glycan-asparagine catabolite detectable in patient samples, which is why this node is named for catabolites rather than for free oligosaccharides alone.
Loss of Deglycosylation-Dependent Substrate Activation
effector
An NGLY1-only branch, not part of the shared chain. Peptide:N-glycanase activates the ER-associated transcription factor NFE2L1/Nrf1 by editing its sequence - glycosylated asparagines are converted to aspartate - and only the edited protein assembles the coactivator complex that drives proteasome subunit gene expression. Without the edit, the cell cannot mount the proteasome bounce-back response when the proteasome is compromised. Nrf proteins are the only transcription factors known to be activated this way, so this is a narrow but mechanistically specific branch. Attach a conformer here only with direct evidence of the activation step, not on the strength of a downstream proteasome or oxidative-stress phenotype.
Downstream
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Neurodevelopmental and Multisystem Dysfunction
A candidate route from the sequence-editing defect to the clinical phenotype. It is a hypothesis: no reported work connects failed Nrf1 activation to any specific feature of human disease.
Show evidence (3 references)
"Here, we demonstrated that sequence editing of the ninth N-glycosylation site (Asn574) in human Nrf1 is required for proteasome gene expression in HeLa cells."
Pins the requirement to a specific edited residue and a specific transcriptional output.
"Editing of Asn574 is essential for interaction with host cell factor C1 and O-GlcNAc transferase, which is required for Nrf1 chromatin binding and sufficient proteasome expression."
Gives the molecular route from the edit to the transcriptional output.
"NGLY1 is also responsible for the activation of a transcription factor, NFE2L1, which participates in several stress responses, including regulation of proteasome subunit expression and oxidative stress."
Independent review statement of the activation function and its two stress-response outputs.
Neurodevelopmental and Multisystem Dysfunction
consequence
The shared clinical shape of the congenital disorders of deglycosylation: a multisystem neurodevelopmental disorder with global developmental delay and intellectual disability, dysmorphic features, and structural brain anomalies. Conforming disorder entries substitute their own specific features - a hyperkinetic movement disorder, alacrima, transaminase elevation and peripheral neuropathy in the peptide:N-glycanase arm; polymicrogyria, tongue hamartoma and posterior-fossa hypoplasia in the alpha-mannosidase arm - which are not shared and should not be inherited from this node.
Show evidence (2 references)
"NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease."
The multisystem shape of the peptide:N-glycanase arm.
"variable degrees of intellectual disability"
The shared neurodevelopmental component in the alpha-mannosidase arm.