Produção Nacional
Revisado por pares
GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms
2017; Elsevier BV; Volume: 92; Linguagem: Inglês
10.1016/j.biocel.2017.09.006
ISSN1878-5875
AutoresNataniel Floriano Ludwig, Renata Voltolini Velho, Fernanda Sperb‐Ludwig, Angelina Xavier Acosta, Erlane Marques Ribeiro, Chong Ae Kim, Dafne Dain Gandelman Horovitz, Raquel Boy, Maria Juliana Rodovalho-Doriqui, Charles Marques Lourenço, Emerson Santana Santos, Thomas Braulke, Sandra Pohl, Ida Vanessa Döederlein Schwartz,
Tópico(s)Glycosylation and Glycoproteins Research
ResumoMucolipidoses (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.
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