Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene - PubMed (original) (raw)

Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene

Mariko Kudo et al. Am J Hum Genet. 2006 Mar.

Abstract

Mucolipidosis II (MLII; I-cell disease) and mucolipidosis IIIA (MLIIIA; classical pseudo-Hurler polydystrophy) 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. To determine whether these diseases are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene (GNPTAB), we sequenced GNPTAB exons and flanking intronic sequences and measured GlcNAc-phosphotransferase activity in patient fibroblasts. We identified 15 different mutations in GNPTAB from 18 pedigrees with MLII or MLIIIA and demonstrated that these two diseases are allelic. Mutations in both alleles were identified in each case, which demonstrated that GNPTAB mutations are the cause of both diseases. Some pedigrees had identical mutations. One frameshift mutation (truncation at amino acid 1171) predominated and was found in both MLII and MLIIIA. This mutation was found in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in MLII and with mild mutations (i.e., mutations allowing the generation of active enzyme) in MLIIIA. Some cases of MLII and MLIIIA were the result of mutations that cause aberrant splicing. Substitutions were inside the invariant splice-site sequence in MLII and were outside it in MLIIIA. When the mutations were analyzed along with GlcNAc-phosphotransferase activity, it was possible to confidently distinguish these two clinically related but distinct diseases. We propose criteria for distinguishing these two disorders by a combination of mutation detection and GlcNAc-phosphotransferase activity determination.

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Figures

Figure 1

Figure 1

Location of mutations on the GlcNAc-phosphotransferase α/β–subunits precursor cDNA. The vertical lines indicate positions of mutations. Numbers below the boxes are exon numbers. Exons that are deleted as a result of splice-site mutations are shaded. An asterisk (*) before the name of a mutation indicates that the frameshift is caused by aberrant splicing. Blackened squares under the cDNA show the frequency of the mutant alleles in this study.

Figure 2

Figure 2

Structure of mutations causing aberrant splicing. Mutations and the resulting mRNA splicing that cause F211X (type 2), FS1085X (type 1), FS1085X (type 2), and FS1202X are shown. Nucleotide substitutions are indicated (arrows). RNA was analyzed by RT-PCR with oligo(dT) or random hexamer primers, and the amplified products were sequenced.

Figure 3

Figure 3

Comparison of frameshift mutations that cause termination at amino acid 211. Deletions in the cDNA sequence change the reading frame in FS211X (type 1) and FS211X (type 2). Nucleotides deleted from the cDNA are boxed. The wild-type reading frame is indicated by spacing; the abnormal reading frame, by brackets.

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References

Web Resources

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for BAC 14951 containing GNPTAB [accession number AC005409], cDNA encoding GlcNAc-phosphotransferase α/β–subunit precursor [accession number AY687932], and the following exons and the flanking intronic sequences: exon 1 [accession number BV677459], exon 2 [accession number BV677460], exons 3 and 4 [accession number BV677461], exon 5 [accession number BV677462], exons 6 and 7 [accession number BV677463], exons 8, 9, and 10 [accession number BV677464], exon 11 [accession number BV677465], exon 12 [accession number BV677466], exon 13 [accession number BV677467], exons 14 and 15 [accession number BV677468], exon 16 [accession number BV677469], exons 17 and 18 [accession number BV677470], exon 19 [accession number BV677471], exon 20 [accession number BV677472], and exon 21 [accession number BV677463])
    1. IUBMB (International Union of Biochemistry and Molecular Biology) Enzyme Nomenclature, http://www.chem.qmul.ac.uk/iubmb/enzyme/ (for accession numbers EC 2.7.8.17 and EC 3.1.4.45)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for MLII, MLIIIA, and MLIIIC)

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