Abstract
Mucolipidosis II α/β, mucolipidosis III α/β, and mucolipidosis III γ are autosomal recessive disorders belonging to the family of lysosomal storage disorders caused by deficiency of the UDP-N-acetylglucosamine, a lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) localized in the Golgi apparatus, which is essential for normal processing and packaging of soluble lysosomal enzymes with initiating the first step of tagging lysosomal enzymes with mannose-6-phosphate (M6P). Mucolipidosis II and III are caused by mutations in the GNPTAB and GNPTG genes, and patients with these diseases are characterized by short stature, skeletal abnormalities, and developmental delay. In this study we report 38 patients with mucolipidosis II and III enrolled in Eastern China during the past 8 years. The diagnosis was made based on clinical characteristics and measurement of plasma lysosomal enzyme activity. Sanger sequencing of GNPTAB and/or GNPTG for all patients and real-time quantitative PCR were performed to confirm the diagnosis. In addition, 11 cases of prenatal mucolipidosis II were diagnosed based on measurement of the enzyme activity in amniotic fluid supernatant and genetic testing of cultured amniotic cells. Based on molecular genetic tests, 30 patients were diagnosed with mucolipidosis II α/β, 6 were diagnosed with III α/β and 2 were diagnosed with III γ. Thirty-seven different GNPTAB gene mutations were identified in 29 patients with mucolipidosis II α/β and six patients with III α/β. These mutations included 22 new mutations (p.W44X, p.E279X, p.W416X, p.W463X, p.Q802X, p.Q882X, p.A34P, p.R334P, p.D408N, p.D534N, p.Y997C, p.D1018V, p.L1025S, p.L1033P, c.88_89delAC, c.890_891insT, c.1150_1151insTTA, c.1523delG, c.2473_2474insA, c.2980_2983delGCCT, c.3094delA, and deletion of exon 9). Four new GNPTG gene mutations were identified (c.13delC, p.Y81X, p.G126R and c.609+1delG) in two mucolipidosis III γ patients. Among the 11 cases of prenatal diagnosis, four were mucolipidosis II fetuses, three were heterozygous, and the remaining four were normal fetuses. This study expands the mutation spectrum of the GNPTAB and GNPTG genes and contributes to specific knowledge of mucolipidosis II/III in a population from Eastern China.
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Acknowledgements
The authors thank Shi-chao Zhao for her assistance with gene molecular analysis. This project was supported by Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20152520), Shanghai Science and Technology Committee (16JC1404600), National Natural Science Foundation of China (81570516 and 81270936), and the National Key Research and Development Program (2016YFC0905100 and 2016YFC0901505).
Author contributions
Hui-wen Zhang and Xue-fan Gu conceived of the study; Yu Wang carried out enzymatic tests and molecular testing and drafted the manuscript; X-fG carried out the enzymatic tests; Hui-wen Zhang, Jun Ye, Lian-shu Han, Wen-juan Qiu, Li-li Liang, and Xiao-lan Gao participated in patient history collection and physical examination; Hui-wen Zhang revised the final manuscript. All authors read and approved the final manuscript.
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Wang, Y., Ye, J., Qiu, Wj. et al. Identification of predominant GNPTAB gene mutations in Eastern Chinese patients with mucolipidosis II/III and a prenatal diagnosis of mucolipidosis II. Acta Pharmacol Sin 40, 279–287 (2019). https://doi.org/10.1038/s41401-018-0023-9
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DOI: https://doi.org/10.1038/s41401-018-0023-9
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