2. Academic Validation
  3. GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms

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.
Nataniel Floriano Ludwig 1,  Renata Voltolini Velho 2,  Fernanda Sperb-Ludwig 1,  Angelina Xavier Acosta 3,  Erlane Marques Ribeiro 4,  Chong A Kim 5,  Dafne Dain Gandelman Horovitz 6,  Raquel Boy 7,  Maria Juliana Rodovalho-Doriqui 8,  Charles Marques Lourenço 9,  Emerson Santana Santos 10,  Thomas Braulke 2,  Sandra Pohl 11,  Ida Vanessa D Schwartz 12
Affiliations

Affiliations

  • 1 Center of Gene Therapy, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; BRAIN Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Post Graduate Program in Genetics and Molecular Biology of Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  • 2 Section Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 3 Universidade Federal da Bahia, Salvador, Brazil.
  • 4 Faculdade de Medicina do Centro Universitário Christus, Fortaleza, Brazil.
  • 5 Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • 6 National Institute for Women's, Children's and Adolescents' Health Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
  • 7 Pediatrics Department, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
  • 8 Juvêncio Mattos Children's Hospital, São Luiz, Maranhão, Brazil.
  • 9 Ribeirão Preto Clinics Hospital, Universidade de São Paulo, Ribeirão Preto, Brazil.
  • 10 Universidade Federal de Sergipe, Lagarto, Brazil.
  • 11 Section Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: [email protected].
  • 12 BRAIN Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Post Graduate Program in Genetics and Molecular Biology of Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Medical Genetics Service of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Electronic address: [email protected].
PMID: 28918368 DOI: 10.1016/j.biocel.2017.09.006
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.

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