Abstract
Abstract GlcNAc-1-phosphotransferase is a hexameric complex formed by subunits α, β, and γ, where the first two are encoded by the GNPTAB gene and the third by the GNPTG gene. Pathogenic variants identified in the GNPTAB gene cause the diseases Mucolipidosis II and III alpha/beta, which are severe and characterized by an overflow of lysosomal hydrolases into the extracellular environment, and their absence in lysosomal compartments causes an accumulation of non-degraded macromolecules. Methodology: a retrospective study that included 32 unrelated Brazilian patients with a clinical and genetic diagnosis of Mucolipidosis II/III alpha/beta. The regional frequency of the altered alleles was determined. Results: The patients were from all regions of Brazil. The most prevalent variants were c.3503_3504del, associated with the severe form of the disease, and c.1208T>C, associated with the milder form. Variant c.3503_3504del is the most frequently found in the Midwest, Northeast, and Southeast regions of Brazil. In the South, 42.8% of the alleles present the c.1196C>T variant. Conclusions: From the perspective of all patients diagnosed with Mucolipidosis II/III in Brazil, it is possible to conclude that different regions present allelic frequencies of specific pathogenic variants, which can be explained by the occurrence of a founding effect or high inbreeding rates.
Highlights
From the perspective of all patients diagnosed with Mucolipidosis II/III in Brazil, it is possible to conclude that different regions present allelic frequencies of specific pathogenic variants, which can be explained by the occurrence of a founding effect or high inbreeding rates
The Mucolipidosis (ML) type II, III alpha/beta, and III gamma are autosomal recessive disorders caused by a defect in the pathway of targeting lysosomal enzymes to lysosome through the mannose-6-phosphate (M6P) signal
Lysosomal enzymes synthesized in the Endoplasmic Reticulum are transported to the Golgi complex, where an enzymatical two-step process generates the M6P signal that guarantees the recognition of lysosomal enzymes by M6P receptors in the trans-Golgi network and subsequent delivery to lysosomal compartments .[1]
Summary
The Mucolipidosis (ML) type II, III alpha/beta, and III gamma are autosomal recessive disorders caused by a defect in the pathway of targeting lysosomal enzymes to lysosome through the mannose-6-phosphate (M6P) signal. Lysosomal enzymes synthesized in the Endoplasmic Reticulum are transported to the Golgi complex, where an enzymatical two-step process generates the M6P signal that guarantees the recognition of lysosomal enzymes by M6P receptors in the trans-Golgi network and subsequent delivery to lysosomal compartments .[1]. The GlcNAc-1-phosphotransferase, responsible for the first step in the M6P pathway, is a cis-Golgi transmembrane resident and hexameric complex formed by α-, β- and γ-subunits (α2β2γ2), codified by two genes. The GNPTG gene is located on chromosome 16p13.3, has 11 exons, and encodes the soluble γ-subunit. The GNPTAB gene is located on chromosome 12q23.3, expands to 21 exons that encode a transmembrane precursor.
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