Genomic organisation of the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTAG) and its mutations in mucolipidosis III

First described by Maroteaux and Lamy in 1966,1 mucolipidosis III (ML III) or pseudo-Hurler polydystrophy (MIM 252600; Online Mendelian Inheritance in Man (OMIM), McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000; http://www.ncbi.nlm.nih.gov/omim/) is a rare autosomal recessive condition resembling Hurler syndrome with no organomegaly or mucopolysacchariduria. Clinical manifestations are variable and progress into adulthood. Bone involvement is slowly progressive and bone pain and disability due to destruction of hip joints are the most frequent and debilitating symptoms. Clinical symptoms include stiffness of the fingers and shoulders, claw hand deformity, short stature, and scoliosis. Mild coarsening of the face with corneal clouding, mild retinopathy, astigmatism, and cardiac valve involvement have also been reported. The radiological findings include moderate to severe dysostosis multiplex with vertebral changes.2 ML III is due to the abnormal trafficking and subcellular localisation of lysosomal enzymes.3–5 Newly synthesised lysosomal enzymes are secreted into the extracellular medium instead of being properly targeted to the lysosomes because they lack a mannose 6-phosphate receptor recognition marker.3,4 The UDP -N- acetylglucosamine-1-phosphotransferase enzyme activity is defective in ML III6 and three complementation groups (A, B, C) have been reported suggesting genetic heterogeneity.7 ML III complementation group C (MIM 252605) is characterised by deficient enzyme activity when assayed with lysosomal glycoproteins as acceptors, but normal activity when assayed with the simple acceptor, α-methylmannoside.6,8 In 1996, Bao et al 9 showed that UDP -N- acetylglucosamine-1-phosphotransferase is a multimeric enzyme made up of three different subunits.9 We have previously ascribed ML III type C to mutations in the UDP -N- acetylglucosamine-1-phosphotransferase gamma subunit gene (GNPTAG) on chromosome 16p.10 Here, we report the genomic structure of this gene and its …