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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.
Am J Hum Genet 2006; 78(3):451-63AJ

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.

Authors+Show Affiliations

Genzyme Corporation, Oklahoma City, OK 73104, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16465621

Citation

Kudo, Mariko, et al. "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." American Journal of Human Genetics, vol. 78, no. 3, 2006, pp. 451-63.
Kudo M, Brem MS, Canfield WM. 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. Am J Hum Genet. 2006;78(3):451-63.
Kudo, M., Brem, M. S., & Canfield, W. M. (2006). 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. American Journal of Human Genetics, 78(3), pp. 451-63.
Kudo M, Brem MS, Canfield WM. 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. Am J Hum Genet. 2006;78(3):451-63. PubMed PMID: 16465621.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kudo,Mariko, AU - Brem,Michael S, AU - Canfield,William M, Y1 - 2006/01/24/ PY - 2005/10/28/received PY - 2005/12/29/accepted PY - 2006/2/9/pubmed PY - 2006/4/28/medline PY - 2006/2/9/entrez SP - 451 EP - 63 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 78 IS - 3 N2 - 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. SN - 0002-9297 UR - https://www.unboundmedicine.com/medline/citation/16465621/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 L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62384-2 DB - PRIME DP - Unbound Medicine ER -