Autosomal-recessive disorder

Every person has two copies of the NGLY1 gene. If one of those two copies is a mutation, a person will be a “carrier”. Being a carrier is not a problem as the one remaining normal copy of the NGLY1 gene is sufficient to produce enough N-glycanase.  But if two carriers meet and have a child, they stand a 25% chance of producing a child with TWO mutated copies of the gene, hence a child that has the disease. 50% of their offspring will be carriers and the remaining 25% will be unaffected.

 

NGLY1 gene lies on Chromosome 3

Amongst the known patients, there is a variety of different mutations dispersed along the NGLY1 gene.  The most common mutation seen in NGLY1 patients is the nonsense mutation p.R401X, or c. 1201A>T, where a change in one codon signals the cell to prematurely stop building the enzyme N-glycanase.

Detailed information provided by Genetics Home Reference:

  • Cytogenetic Location: 3p24.2, which is the short (p) arm of chromosome 3 at position 24.2
  • Molecular Location: base pairs 25,718,944 to 25,790,039 on chromosome 3 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

 

Pathway

In NGLY1 Deficiency, patients have mutations in both copies of the NGLY1 gene. This gene holds the information the body needs to synthesize the enzyme N-glycanase. N-glycanase catalyses the cleaving of N-linked glycans from misfolded glycoproteins and other glycoproteins in the cytosol, before these proteins can be degraded by the proteasome. With mutations in this particular gene, NGLY1 patients produce little or no N-glycanase.

The exact mechanism of harm is not yet understood. One hypothesis is that lacking N-glycanase leaves the body with an impaired capacity to recycle misfolded glycoproteins as outlined above. The misfolded glycoproteins appear to accumulate in the cells of patients which may cause this condition. Another hypothesis is that since N-linked glycans are not being cleaved, they are not available for other crucially important mechanisms in the cell.  And, yet a third hypothesis is that the partially-degraded, misfolded N-linked glycoproteins interfere with the glycosylation processes inside of patient cells.