Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype–phenotype correlation
Takanobu Otomo,T Muramatsu,Tohru Yorifuji,Torayuki Okuyama,Hiroki Nakabayashi,Toshiyuki Fukao,Toshihiro Ohura,Makoto Yoshino,Akemi Tanaka,Nobuhiko Okamoto,Koji Inui,Keiichi Ozono,Norio Sakai +12 more
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TLDR
The results show the effective molecular diagnosis of ML II and III and also provide phenotypic prediction, which is the first and comprehensive report of molecular analysis for ML patients of Japanese origin.Abstract:
Mucolipidosis (ML) II alpha/beta and III alpha/beta are autosomal recessive diseases caused by a deficiency of α and/or β subunits of the enzyme N-acetylglucosamine-1-phosphotransferase, which is encoded by the GNPTAB gene. We analyzed the GNPTAB gene in 25 ML II and 15 ML III Japanese patients. In most ML II patients, the clinical conditions ‘stand alone’, ‘walk without support’ and ‘speak single words’ were impaired; however, the frequency of ‘heart murmur’, ‘inguinal hernia’ and ‘hepatomegaly and/or splenomegaly’ did not differ between ML II and III patients. We detected mutations in GNPTAB in 73 of 80 alleles. Fourteen new mutations were c.914_915insA, c.2089_2090insC, c.2427delC, c.2544delA, c.2693delA, c.3310delG, c.3388_3389insC+c.3392C>T, c.3428_3429insA, c.3741_3744delAGAA, p.R334L, p.F374L, p.H956Y, p.N1153S and duplication of exon 2. Previously reported mutations were p.Q104X, p.W894X, p.R1189X and c.2715+1G>A causing skipping of exon 13. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the severe phenotype. p.F374L, p.N1153S and splicing mutations contributed to the attenuated phenotype, although coupled with nonsense mutation. These results show the effective molecular diagnosis of ML II and III and also provide phenotypic prediction. This is the first and comprehensive report of molecular analysis for ML patients of Japanese origin.read more
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Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering.
Changsoo Kang,Sheikh Riazuddin,Jennifer Mundorff,Donna M. Krasnewich,Penelope L. Friedman,James C. Mullikin,Dennis Drayna +6 more
TL;DR: Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.
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Mannose-6-phosphate pathway: A review on its role in lysosomal function and dysfunction
TL;DR: This review synthesizes the current knowledge on each of the major proteins involved in the M6P-dependent pathway, highlighting the lysosomal storage disorders associated to GlcNAc-1-phosphotransferase loss of function: mucolipidosis type II and III.
Journal ArticleDOI
Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands
Sara S. Cathey,Jules G. Leroy,Tim Wood,Karisa Eaves,Richard J. Simensen,Mariko Kudo,Roger E. Stevenson,Michael J. Friez +7 more
TL;DR: Clinical, biochemical and molecular findings in 61 probands, including 42 novel mutations in GNPTAB, provide a broad perspective of mucolipidoses II and III, andple clinical information improves criteria for delineation of ML II and ML III.
Journal ArticleDOI
Mannose phosphorylation in health and disease.
Katrin Kollmann,Sandra Pohl,Katrin Marschner,Marisa Encarnação,Imme Sakwa,Stephan Tiede,Ben J. Poorthuis,Torben Lübke,Sven Müller-Loennies,Stephan Storch,Thomas Braulke +10 more
TL;DR: The generation of recombinant single-chain antibody fragments against M6P residues and of new mouse models of MLII and MLIII will have considerable impact to provide deeper insight into the cell biology of lysosomal dysfunctions and the pathomechanisms underlying these lysOSomal disorders.
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Genetics of speech and language disorders.
Changsoo Kang,Dennis Drayna +1 more
TL;DR: The discovery of mutations in the FOXP2 gene led to a new avenue of investigation into the substrates and mechanisms that underlie human speech development, and linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci.
References
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Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase.
Stephan Tiede,Stephan Storch,Torben Lübke,Bernhard Henrissat,Ruth Bargal,Annick Raas-Rothschild,Thomas Braulke +6 more
TL;DR: Evidence is provided that GNPTA encodes a subunit of GlcNAc-1-phosphotransferase defective in individuals with ML II, which is a fatal lysosomal storage disorder resulting from defects in the multimeric Glcnac- 1-ph phosphate-basedase responsible for the initial step in the generation of the mannose 6- phosphate recognition marker.
Journal ArticleDOI
Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)
Annick Raas-Rothschild,Valérie Cormier-Daire,Ming Bao,Emmanuelle Génin,Rémi Salomon,Kevin Brewer,Marsha Zeigler,Hanna Mandel,Steve Toth,Bruce A. Roe,Arnold Munnich,William M. Canfield +11 more
TL;DR: This is to the authors' knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition.
Journal ArticleDOI
Mucolipidosis II (I-Cell Disease) and Mucolipidosis IIIA (Classical Pseudo-Hurler Polydystrophy) Are Caused by Mutations in the GlcNAc-Phosphotransferase α/β–Subunits Precursor Gene
TL;DR: Criteria for distinguishing these two disorders by a combination of mutation detection and GlcNAc-phosphotransferase activity determination is proposed and it is possible to confidently distinguish these two clinically related but distinct diseases.
Journal ArticleDOI
Bovine UDP-N-acetylglucosamine:Lysosomal-enzyme N-Acetylglucosamine-1-phosphotransferase I: PURIFICATION AND SUBUNIT STRUCTURE *
TL;DR: The data indicate that bovine GlcNAc-phosphotransferase is a 540,000-Da complex composed of disulfide-linked homodimers of 166-000- and 51-Thousands-Da subunits and two identical, noncovalently associated 56,000+ subunits.
Journal ArticleDOI
The alpha- and beta-subunits of the human UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase [corrected] are encoded by a single cDNA.
Mariko Kudo,Ming Bao,Anil D'Souza,Anil D'Souza,Fu Ying,Huaqin Pan,Bruce A. Roe,William M. Canfield,William M. Canfield +8 more
TL;DR: The completion of cloning all three subunits of GlcNAc-phosphotransferase allows expression of recombinant enzyme and dissection of lysosomal targeting disorders.