GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms PMID: 28918368

RQC and Longevity Regulation

2026-09-03

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

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].

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.