Three novel homozygous mutations in the GNPTG gene that cause mucolipidosis type III gamma
Introduction
Mucolipidosis type III, originally called a variant of pseudo-Hurler polydystrophy, is an autosomal recessive disease that results from a deficiency of the membrane-bound enzyme UDP-GlcNAc-1-phosphotransferase (Tappino et al., 2009). This enzyme is responsible for the initial step in the synthesis of the mannose 6-phosphate (M6P) recognition markers on high mannose-type oligosaccharides in the Golgi. A lack of GlcNAc-1-phosphotransferase leads to the M6P marker losing its function. Without M6P, the trafficking process that moves the lysosomal hydrolases to lysosomes is impaired (Tappino et al., 2009).
The GlcNAc-1-phosphotransferase is composed of a 540-kDa α 2-β 2-γ 2 hexameric complex. Two genes, GNPTAB (Raas-Rothschild et al., 2000) and GNPTG (Kudo et al., 2005, Tiede et al., 2005), encode α/β- and γ-subunits of the GlcNAc-1-phosphotransferase, respectively. The GNPTAB is located on chromosome 12q23.3, contains 21 exons spanning 85 kb and encodes a protein of 1256 amino acids with a predicted molecular mass of 144 kDa (a/b precursor) (Kudo et al., 2005, Raas-Rothschild et al., 2000, Tiede et al., 2005, Tiede et al., 2006). A mutation of the GNPTAB gene will cause MLIII alpha/beta (α/β) (MIM #252600). The GNPTG gene (GNPTG) is located on chromosome 16 and was discovered in 2000. GNPTG contains 11 exons and encodes a soluble protein made up of 305 amino acids with a predicted molecular mass of 34 kDa. Mutation of the GNPTG gene is responsible for MLIII gamma (γ) (MIM #252605). It is believed that the γ-subunit is capable of forming disulfide-linked dimers, and the α/β-precursor appears to be a prerequisite for the catalytic activity of the enzyme (Pohl et al., 2009).
Clinically, MLIII α/β and MLIII γ are both rare diseases and are indistinguishable. The typical clinical symptoms include progressive joint stiffness, short stature, scoliosis and mild mental retardation. Most patients also exhibit cardiac valve involvement and experience bone pain and disability because of destruction of the hip joints. Moderate to severe dysostosis multiplex with vertebral changes is evident upon radiological examination (Pohl et al., 2009, Zarghooni and Dittakavi, 2009).
Here we report two unique Chinese children with MLIII gamma caused by three novel homozygous mutations in the GNPTG gene.
Section snippets
Patients
The study was approved by the Peking Union Medical College Hospital Institutional Review Board, and peripheral blood samples were collected from the patients and their parents with informed consent.
Three affected children were included in the study, two girls and one boy that were 13, 12 and 17 years of age. The participants are from unrelated intermarried families. All of the children were born normally. They were admitted to our clinic for progressive joint stiffness a minimum of nine years
Results
The plasma activity of the two lysosomal hydrolases (β-d-glucuronidase and α-d-mannosidase) in all affected patients was significantly increased over its activity in the controls (18.8–22.4-fold for β-d-glucuronidase and 12.4–13.7-fold for α-d-mannosidase) (Table 1).
Three novel homozygous mutations in the GNPTG gene were found in the affected consanguineous children. In the 13-year-old girl, an adenine was substituted for the guanine at nucleotide 425 in exon seven (c.425G>A; p.Cys142Val); in
Discussion
Prior to June 2013, a total of 25 mutations in the GNPTG gene from 44 patients had been reported, including 10 deletions, five insertions, four missense mutations, two nonsense mutations and four splicing mutations. All of the mutations are randomly distributed in each exon, without the presence of a distinct hot spot (Encarnacao et al., 2009, Gao et al., 2011, Kang et al., 2010, Persichetti et al., 2009, Pohl et al., 2010, Raas-Rothschild et al., 2000, Raas-Rothschild et al., 2004, Zarghooni
Conclusions
In conclusion, we report three novel GNPTG mutations in three Chinese children with the typical MLIII phenotype. Although the correlation between the genotype and the phenotype of MLIII is still unclear, the identification of new mutations could expand the spectrum of GNPTG gene mutations.
Competing interests
The authors declare that they have no competing interest.
Authors' contributions
SL and ZQ conceived the study. SL and ZQ recruited and made the clinical diagnoses of the patients and performed the genetic counseling and follow up. SL performed the DNA mutation analysis. WZ performed the lysosome enzyme analyses. SL researched the literature and reviewed and prepared the manuscript. SL and ZQ edited and coordinated the manuscript. All of the authors discussed, read and approved the manuscript.
Acknowledgments
We thank all patients and their family members who participated in this study.
This work was supported by a grant from the National Natural Science Foundation of China (No. 81241032) and the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (No. 2012BAI09B00).
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The first author.