Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III

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Di Lorenzo, Giorgia ^{[1, 2]} ; Westermann, Lena M. ^[1] ; Yorgan, Timur A. ^[1] ; Stuerznickel, Julian ^[1] ; Ludwig, Nataniel F. ^{[3, 4]} ; Ammer, Luise S. ^[5] ; Baranowsky, Anke ^{[1, 6]} ; Ahmadi, Shiva ^[7] ; Pourbarkhordariesfandabadi, Elham ^[7] ; Breyer, Sandra R. ^{[8, 5, 9]} ; Board, Tim N. ^[10] ; Foster, Anne ^[11] ; Mercer, Jean ^[11] ; Tylee, Karen ^[11] ; Velho, Renata Voltolini ^[1] ; Schweizer, Michaela ^[12] ; Renne, Thomas ^[13] ; Braulke, Thomas ^[1] ; Randon, Devora N. ^{[3, 4]} ; Sperb-Ludwig, Fernanda ^{[3, 4]} ; de Camargo Pinto, Louise Lapagesse ^[14] ; Moreno, Carolina Araujo ^[15] ; Cavalcanti, Denise P. ^[15] ; Amling, Michael ^[1] ; Kutsche, Kerstin ^[16] ; Winter, Dominic ^[7] ; Muschol, Nicole M. ^[5] ; Schwartz, Ida V. D. ^{[3, 4]} ; Rolvien, Tim ^{[1, 8]} ; Danyukova, Tatyana ^[1] ; Schinke, Thorsten ^[1] ; Pohl, Sandra ^{[1, 5]}

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^[1] Univ Med Ctr Hamburg Eppendorf, Dept Osteol & Biomech, Hamburg - Germany

^[2] Telethon Inst Genet & Med TIGEM, Naples - Italy

^[3] Univ Fed Rio Grande do Sul, Post Grad Program Genet & Mol Biol, Porto Alegre, RS - Brazil

^[4] Hosp Clin Porto Alegre, Clin Expt Res Ctr, BRAIN Lab, Porto Alegre, RS - Brazil

^[5] Univ Med Ctr Hamburg Eppendorf, Int Ctr Lysosomal Disorders, Hamburg - Germany

^[6] Univ Med Ctr Hamburg Eppendorf, Dept Trauma & Orthoped Surg, Hamburg - Germany

^[7] Univ Bonn, Med Fac, Inst Biochem & Mol Biol, Bonn - Germany

^[8] Univ Med Ctr Hamburg Eppendorf, Dept Orthoped, Hamburg - Germany

^[9] Childrens Hosp Altona, Dept Pediat Orthoped, Hamburg - Germany

^[10] Wigan & Leigh NHS Trust, Ctr Hip Surg, Appley Bridge, Wigan - England

^[11] Manchester Univ NHS Fdn Trust, St Marys Hosp, Manchester, Lancs - England

^[12] Univ Med Ctr Hamburg Eppendorf, Ctr Mol Neurobiol, Hamburg - Germany

^[13] Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem & Lab Med, Hamburg - Germany

^[14] Childrens Hosp Joana Gusmao, Florianopolis, SC - Brazil

^[15] Univ Estadual Campinas, Dept Med Genet, Skeletal Dysplasia Grp, Campinas - Brazil

^[16] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Hamburg - Germany

• Tipo de documento: Artigo Científico
• Fonte: Genetics in Medicine; v. 23, n. 12 AUG 2021.
• Citações Web of Science: 0

Resumo

Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptg(ko)and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptg(ko) bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptg(ko) mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy. (AU)

• Processo FAPESP: 15/22145-6 - Contribuição ao estudo clínico-etiológico das displasias esqueléticas e disostoses no Brasil
• Beneficiário: Denise Pontes Cavalcanti
• Modalidade de apoio: Auxílio à Pesquisa - Regular