Submission Details

GNPTG was first reported in relation to GNPTG-mucolipidosis (also known as mucolipidosis type III gamma), an autosomal recessive disorder of lysosomal hydrolase trafficking, in 2000 (Raas-Rothschild et al, PMID: 10712439).

GNPTG encodes the gamma subunit of GlcNAc‐1‐phosphotransferase, a hexameric enzyme composed of membrane‐bound alpha‐ and beta‐subunits which are synthesized as a common alpha/beta‐precursor encoded by GNPTAB, in addition to the soluble gamma subunit encoded by GNPTG. GlcNAc-1-phosphotransferase catalyzes the first step of the formation of mannose 6-phosphate (M6P) on specific soluble lysosomal hydrolases. M6P is essential for the trafficking of these lysosomal enzymes from the trans-Golgi network to the lysosomes via M6P receptors. Without M6P, newly synthesized lysosomal enzymes are missorted into the extracellular space and are unable to breakdown specific substrates in lysosomes (for reviews, see Velho et al, 2019, PMID: 30882951; and Khan and Tomatsu, 2020, PMID: 32957425). As a result, various macromolecules accumulate in the lysosomes in different tissues causing the characteristic symptoms of mucolipidosis.

Biallelic variants in GNPTG are reported in individuals with mucolipiosis type III gamma. This condition is characterized by gradual mild coarsening of facial features, spinal deformities including scoliosis and hyperlordosis, genu valgum, restricted joint mobility, short stature, and characteristic radiographic findings. Most patients have normal intellectual capacity, and organomegaly is not present. Mucolipidosis type II gamma is typically milder and less rapidly progressive than mucolipidosis type II, which is caused by variants in GNPTAB (Raas-Rothschild & Spiegel, 2019, PMID: 20301784).

About 50 different GNPTG variants have been identified in individuals with mucolipiosis type III gamma, about 80% of which result in formation of a premature stop codon (Velho et al, 2019, PMID: 30882951). The mechanism of pathogenicity is loss of function. Seventeen variants (including nonsense, frameshift, splice site, missense, in-frame deletion) reported in 12 probands in 4 publications (Raas-Rothschild et al, 2000, PMID: 10712439; Raas-Rothschild et al, 2004, PMID: 15060128; Persichetti et al, 2009, PMID: 19370764; Velho et al, 2014, PMID: 27896079) are included in this curation in addition to segregation data from a large, consanguineous family (Raas-Rothschild et al, 2000, PMID: 10712439). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by the biochemical function of the gene product, which is consistent with the biochemical and clinical features of mucolipidosis type III gamma (Lee et al, 2007, PMID: 17652091; Di Lorenzo et al, 2018, PMID: 29773673), rescue in patient cells (Zarghooni et al, 2009, PMID: 19938078), and the features reported in Gnptg knock out mouse and zebrafish models (Vogel et al, 2009, PMID: 19261645; Idol et al, 2014, PMID: 25314316; Flannagan-Steet et al, 2016, PMID: 27241848).

In summary, GNPTG is definitively associated with autosomal recessive GNPTG-mucolipidosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP (SOP v9) on December 28, 2022.