Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III – identification of eight novel mutations

Authors

  • M Encarnação,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • a L Lacerda,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • a R Costa,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • a MJ Prata,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • b MF Coutinho,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • a H Ribeiro,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • a L Lopes,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • a M Pineda,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • c J Ignatius,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • d H Galvez,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • c A Mustonen,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • d P Vieira,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • e MR Lima,

    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author
  • and a S Alves a

    Corresponding author
    1. a National Health Institute Dr Ricardo Jorge, Center of Medical Genetics Dr Jacinto Magalhães and bInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, cDepartment of Neurology, Hospital Sant Joan de Deu and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain, and dDepartments of Clinical Genetics and eChild Neurology, Oulu University Hospital, Oulu, Finland
    Search for more papers by this author

Sandra Alves, Centro de Genética Médica Jacinto Magalhães, Praça Pedro Nunes, 88, 4099-028 Porto, Portugal.
Tel.: +351 226070300;
fax: +351 226070399;
e-mail: sandra.alves@igm.min-saude.pt; alvessandra@hotmail.com

Abstract

Mucolipidosis II (ML II) and mucolipidosis III (ML III) are diseases in which the activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent or reduced, respectively. In the absence of mannose phosphorylation, trafficking of lysosomal hydrolases to the lysosome is impaired. In these diseases, mistargeted lysosomal hydrolases are secreted into the blood, resulting in lysosomal deficiency of many hydrolases and a storage-disease phenotype. GlcNAc-phosphotransferase is a multimeric transmembrane enzyme composed of three subunits (α, β and γ) encoded by two genes –GNPTAB and GNPTG. Defects in GNPTAB result in ML II and III whereas mutations in GNPTG were only found in ML III patients. We have performed a molecular analysis of the GNPTAB and GNPTG genes in 13 mucolipidosis II and III patients (10 Portuguese, one Finnish, one Spanish of Arab origin and one Indian). Mutations were identified by the study of both cDNA and gDNA. The GNPTAB and GNPTG mRNA expressions were determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The study led to the identification of 11 different mutations. Eight of these mutations are novel, six in the GNPTAB gene [c.121delG (V41FfsX42), c.440delC (A147AfsX5), c.2249_50insA (N750KfsX8), c.242G>T (W81L), c.1208T>C (I403T) and c.1999G>T (p.E667X)] and two in the GNPTG gene [c.610-1G>T and c.639delT (F213LfsX7)]. With regard to the mRNA expression studies, the values obtained by qRT-PCR indicate the possible existence of feedback regulation mechanisms between α/β and the γ subunits.

Ancillary