Analyses of disease-related GNPTAB mutations define a novel GlcNAc-1-phosphotransferase interaction domain and an alternative site-1 protease cleavage site

Human Molecular Genetics
R V VelhoSandra Pohl

Abstract

Mucolipidosis II (MLII) and III alpha/beta are autosomal-recessive diseases of childhood caused by mutations in GNPTAB encoding the α/β-subunit precursor protein of the GlcNAc-1-phosphotransferase complex. This enzyme modifies lysosomal hydrolases with mannose 6-phosphate targeting signals. Upon arrival in the Golgi apparatus, the newly synthesized α/β-subunit precursor is catalytically activated by site-1 protease (S1P). Here we performed comprehensive expression studies of GNPTAB mutations, including two novel mutations T644M and T1223del, identified in Brazilian MLII/MLIII alpha/beta patients. We show that the frameshift E757KfsX1 and the non-sense R587X mutations result in the retention of enzymatically inactive truncated precursor proteins in the endoplasmic reticulum (ER) due to loss of cytosolic ER exit motifs consistent with a severe clinical phenotype in homozygosity. The luminal missense mutations, C505Y, G575R and T644M, partially impaired ER exit and proteolytic activation in accordance with less severe MLIII alpha/beta disease symptoms. Analogous to the previously characterized S399F mutant, we found that the missense mutation I403T led to retention in the ER and loss of catalytic activity. Substitution of further ...Continue Reading

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Citations

Sep 20, 2015·Human Molecular Genetics·Raffaella De PaceSandra Pohl
Apr 3, 2020·Journal of Pediatric Endocrinology & Metabolism : JPEM·Muhammad Aman KhanMuhammad Naeem
May 18, 2016·Journal of Pediatric Endocrinology & Metabolism : JPEM·Feyzollah Hashemi-GorjiMohammad Miryounesi
Jul 10, 2020·Journal of the American Society of Nephrology : JASN·Wiebke SachsCatherine Meyer-Schwesinger
Dec 15, 2018·Molecular Genetics & Genomic Medicine·Alexander GheldofLinda De Meirleir
Aug 4, 2021·Journal, Genetic Engineering & Biotechnology·Mona L EssawiSamia A Temtamy
Jul 12, 2017·Biochimica Et Biophysica Acta. Molecular Cell Research·Renata Voltolini VelhoSandra Pohl

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
transfections
PCR
Protein Assay
electrophoresis
FCS
transfection

Software Mentioned

PrimerX
SeqLab
Image Lab

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