GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms

Int J Biochem Cell Biol. 2017 Nov:92:90-94. doi: 10.1016/j.biocel.2017.09.006. Epub 2017 Sep 14.

Abstract

Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the α⁄β-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p.Q278Kfs*3, p.H588Qfs*27, p.N642Lfs*10 and p.Y1111*. Expression analysis by western blotting and immunofluorescence microscopy revealed that the mutant α⁄β-subunit precursor p.D76G is retained in the endoplasmic reticulum whereas the mutant p.S385L is correctly transported to the cis-Golgi apparatus and proteolytically processed. Both mutations lead to complete loss of GlcNAc-1-phosphotransferase activity, consistent with the severe clinical MLII phenotype of the patients. Our study expands the genotypic spectrum of MLII and provides novel insights into structural requirements to ensure GlcNAc-1-phosphotransferase activity.

Keywords: Genotype-phenotype relation; Lysosomal storage disorder; Mannose 6-phosphate; Missense mutations; Site-1 protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Female
  • Genotype
  • Humans
  • Infant
  • Loss of Function Mutation*
  • Male
  • Mucolipidoses / enzymology*
  • Mucolipidoses / genetics*
  • Mutation, Missense*
  • Transferases (Other Substituted Phosphate Groups) / genetics*
  • Transferases (Other Substituted Phosphate Groups) / metabolism
  • Young Adult

Substances

  • Transferases (Other Substituted Phosphate Groups)
  • GNPTAB protein, human