Submission Details

GNPTAB was first reported in relation to GNPTAB-mucolipidosis, an autosomal recessive disorder of lysosomal hydrolase trafficking, in 2005 (Tiede et al, PMID: 16094673; Paik et al, PMID: 16116615; Tiede et al, PMID: 16200072).

GNPTAB encodes a precursor protein that is subsequently cleaved into the alpha and beta subunits of UDP-N-acetylglucosamine-1-phosphotransferase, a hexameric enzyme composed of 2 alpha, 2 beta, and 2 gamma subunits. This enzyme 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 mis-sorted 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 resulting in a spectrum of clinical symptoms (see LeRoy et al, 2019, PMID: 20301728 for review).

At the most severe end of the GNPTAB-mucolipidosis clinical spectrum, individuals with mucolipiosis type II (also known as I-cell disease, Pacman disease; MIM# 252500; MONDO:0009650) have progressive features, evident at birth, and usually resulting in death in childhood. Characteristic features include skeletal abnormalities, postnatal growth retardation, contractures of the large joints, coarse facial features, hypertrophic gingiva, cardiac involvement (such as thickening of the mitral valve or aortic valve), and progressive respiratory insufficiency, which is the most common cause of death. At the milder end of the clinical spectrum, ML III alpha/beta (also known as Pseudo-Hurler-polydystrophy; MIM # 252600; MONDO:0018931) usually presents at around age 3 years with growth delay, short stature, joint stiffness, mild coarsening of facial features, and cognitive ability ranging from normal to mild intellectual disability. Death usually occurs in early to mid-adulthood from cardiorespiratory problems. Patients with symptoms intermediate between ML II and MLL III alpha/beta (also known as Webb mucolipidosis) have also been reported (LeRoy et al, 2019, PMID: 20301728). These disorders are all inherited in an autosomal recessive manner and all are caused by UDP-N-acetylglucosamine-1-phosphotransferase deficiency due to loss of function of the alpha/beta subunits. Therefore, for the purposes of this curation, these disorders have been lumped under "UDP-N-acetylglucosamine-1-phosphotransferase subunit alpha/beta deficiency" (MONDO:0100122; synonym GNPTAB-related disorders). In addition to this condition, recent studies have reported that variants in GNPTAB are associated with non-syndromic stuttering. The affected individuals were heterozygous, but the inheritance pattern is unclear (PMID: 20301728 and references therein). Stuttering has not been observed in individuals with GNPTAB-mucolipidosis (PMID: 20301728). Therefore, these data are not included in the current curation.

Over 250 different GNPTAB variants have been identified in individuals with GNPTAB-mucolipidosis (Velho et al, 2019, PMID: 30882951). The mechanism of pathogenicity is loss of function. Nineteen variants (including nonsense, frameshift, splicing, missense) reported in 14 probands in 4 publications (Paik et al, 2005, PMID: 16116615; Heo et al, 2012, PMID: 23227064; Cury et al, 2013, PMID: 23566849; Mao et al, 2022, PMID: 35463894) are included in this curation. Of note, the most common variant worldwide, c.3503_3504delTC, is a founder variant in the Saguenay-Lac-Saint-Jean region in Quebec (Plante et al, 2008, PMID: 18190596; LeRoy et al, 2019, PMID: 20301728). 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 UDP-N-acetylglucosamine-1-phosphotransferase subunit alpha/beta deficiency (Kudo et al, 2005, PMID: 16120602; van Meel et al, 2016, PMID: 26833567), data from a GNPTAB siRNA knockdown study (Tiede et al, PMID: 34116066), and the clinical and biochemical features reported in a Gnptab knock out mouse (Gelfman et al, 2007, PMID: 17962477; Vogel et al, 2009, PMID: 19261645) and mouse with a knock-in GNPTAB patient variant (Koehne et al, 2017, PMID: 27239697). More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached.

In summary, GNPTAB is definitively associated with autosomal recessive GNPTAB-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 on April 28, 2023 (SOP v9).

Data provided by the ClinGen Prenatal GCEP from November 19, 2024 secondary analysis:

Prenatal phenotypes described in the literature in association with GNPTAB include skeletal dysplasias like short long bones, dysmorphic facial features, and growth restriction. Three cases are reported with nonsense, frameshift, and splicing variants (PMID: 23227064, 30105123). At this time of curation, no cases with fetal hydrops has been reported. There are only a few cases reported with prenatal phenotypes and molecular genetic confirmation published.

GNPTAB was first reported in relation to GNPTAB-mucolipidosis, an autosomal recessive disorder of lysosomal hydrolase trafficking, in 2005 (Tiede et al, PMID: 16094673; Paik et al, PMID: 16116615; Tiede et al, PMID: 16200072).

GNPTAB encodes a precursor protein that is subsequently cleaved into the alpha and beta subunits of UDP-N-acetylglucosamine-1-phosphotransferase, a hexameric enzyme composed of 2 alpha, 2 beta, and 2 gamma subunits. This enzyme 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 mis-sorted 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 resulting in a spectrum of clinical symptoms (see LeRoy et al, 2019, PMID: 20301728 for review).

At the most severe end of the GNPTAB-mucolipidosis clinical spectrum, individuals with mucolipiosis type II (also known as I-cell disease, Pacman disease; MIM# 252500; MONDO:0009650) have progressive features, evident at birth, and usually resulting in death in childhood. Characteristic features include skeletal abnormalities, postnatal growth retardation, contractures of the large joints, coarse facial features, hypertrophic gingiva, cardiac involvement (such as thickening of the mitral valve or aortic valve), and progressive respiratory insufficiency, which is the most common cause of death. At the milder end of the clinical spectrum, ML III alpha/beta (also known as Pseudo-Hurler-polydystrophy; MIM # 252600; MONDO:0018931) usually presents at around age 3 years with growth delay, short stature, joint stiffness, mild coarsening of facial features, and cognitive ability ranging from normal to mild intellectual disability. Death usually occurs in early to mid-adulthood from cardiorespiratory problems. Patients with symptoms intermediate between ML II and MLL III alpha/beta (also known as Webb mucolipidosis) have also been reported (LeRoy et al, 2019, PMID: 20301728). These disorders are all inherited in an autosomal recessive manner and all are caused by UDP-N-acetylglucosamine-1-phosphotransferase deficiency due to loss of function of the alpha/beta subunits. Therefore, for the purposes of this curation, these disorders have been lumped under "UDP-N-acetylglucosamine-1-phosphotransferase subunit alpha/beta deficiency" (MONDO:0100122; synonym GNPTAB-related disorders). In addition to this condition, recent studies have reported that variants in GNPTAB are associated with non-syndromic stuttering. The affected individuals were heterozygous, but the inheritance pattern is unclear (PMID: 20301728 and references therein). Stuttering has not been observed in individuals with GNPTAB-mucolipidosis (PMID: 20301728). Therefore, these data are not included in the current curation.

Over 250 different GNPTAB variants have been identified in individuals with GNPTAB-mucolipidosis (Velho et al, 2019, PMID: 30882951). The mechanism of pathogenicity is loss of function. Nineteen variants (including nonsense, frameshift, splicing, missense) reported in 14 probands in 4 publications (Paik et al, 2005, PMID: 16116615; Heo et al, 2012, PMID: 23227064; Cury et al, 2013, PMID: 23566849; Mao et al, 2022, PMID: 35463894) are included in this curation. Of note, the most common variant worldwide, c.3503_3504delTC, is a founder variant in the Saguenay-Lac-Saint-Jean region in Quebec (Plante et al, 2008, PMID: 18190596; LeRoy et al, 2019, PMID: 20301728). 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 UDP-N-acetylglucosamine-1-phosphotransferase subunit alpha/beta deficiency (Kudo et al, 2005, PMID: 16120602; van Meel et al, 2016, PMID: 26833567), data from a GNPTAB siRNA knockdown study (Tiede et al, PMID: 34116066), and the clinical and biochemical features reported in a Gnptab knock out mouse (Gelfman et al, 2007, PMID: 17962477; Vogel et al, 2009, PMID: 19261645) and mouse with a knock-in GNPTAB patient variant (Koehne et al, 2017, PMID: 27239697). More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached.

In summary, GNPTAB is definitively associated with autosomal recessive GNPTAB-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 on April 28, 2023 (SOP v9).