Structural basis of the GM2 gangliosidosis B variant

Matsuzawa, Fumiko; Aikawa, Sei-ichi; Sakuraba, Hitoshi; Lan, Hoàng Thị; Tanaka, Akemi; Ohno, Kousaku; Sugimoto, Yoshimi; Ninomiya, Haruaki; Doi, Hirofumi

doi:10.1007/s10038-003-0082-7

Cited by 15 publications

(9 citation statements)

References 27 publications

(29 reference statements)

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“…In R499C, the cysteine residue might create an illegitimate disulfide bridge in the protein with a resultant disruption of the normal three-dimensional structure, causing a more severe clinical phenotype than in R499H (Akli et al, 1993). Our study of the structural analysis by molecular modeling software showed no drastic structural changes in a subunit polypeptides with R499C/H (Matsuzawa et al, 2003), which was consistent with the mild clinical phenotypes.…”

Section: Discussionsupporting

confidence: 72%

Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form

et al. 2003

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Eight mutations of the a subunit of b-hexosaminidase A gene (HEXA) were identified in eight patients with GM2 gangliosidosis variant B. They were five missense mutations, two splice-site mutations, and one two-base deletion. Five of them, R252L (CGT fi CTT), N295S (AAT fi AAC), W420C (TGG fi TGT), IVS 13, +2A fi C, and del 265-266AC (exon 2), were novel mutations responsible for infantile acute form of GM2 gangliosidosis. Two missense mutations, R499H and R499C, were found in one allele of two patients with attenuated phenotypes. The patient with R499C showed a late infantile form, and the other patient with R499H showed a juvenile form. These two mutations have been reported previously in the patients of other ethnic groups, and they have been known to cause attenuated phenotypes. The milder phenotypes of GM2 gangliosidosis variant B, different from the infantile acute form, have not been reported so far in Japan, and this is the first report of Japanese patients with attenuated phenotypes and their molecular analysis.

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Section: Discussionsupporting

confidence: 72%

Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form

et al. 2003

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“…The root-mean-square graduate value was set at 0.05 kcal/mol Å . Then, each mutant model was superimposed on the wild-type structure based on the Ca atoms by the least-square-mean fitting method (Kabsch 1976(Kabsch , 1978Sakuraba et al 2000Sakuraba et al , 2004Matsuzawa et al 2003Matsuzawa et al , 2005. We defined that the structure was influenced by an amino acid substitution when the position of an atom in a mutant differed from that in the wild type by more than the cutoff distance (0.15 Å ) based on the total RMSD, as described previously (Matsuzawa et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Structural study on mutant α-l-iduronidases: insight into mucopolysaccharidosis type I

et al. 2008

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To elucidate the basis of mucopolysaccharidosis type I (MPS I), we constructed structural models of mutant a-L-iduronidases (IDUAs) resulting from 33 amino acid substitutions that lead to MPS I (17 severe, eight intermediate, and eight attenuated). Then, we examined the structural changes in the enzyme protein by calculating the number of atoms affected and determined the root-meansquare distance (RMSD) and the solvent-accessible surface area (ASA). In the severe MPS I group, the number of atoms influenced by a mutation and the average RMSD value were larger than those in the attenuated group, and the residues associated with the mutations identified in the severe group tended to be less solvent accessible than those in the attenuated group. The clinically intermediate phenotype group exhibited intermediate values for the numbers of atoms affected, RMSD, and ASA between those in the severe group and those in the attenuated group. The results indicated that large structural changes had occurred in the core region in the severe MPS I group and small ones on the molecular surface in the attenuated MPS I group. Color imaging revealed the distributions and degrees of the structural changes caused by representative mutations for MPS I. Thus, structural analysis is useful for elucidating the basis of MPS I. As there was a difference in IDUA structural change between the severe MPS I group and the attenuated one, except for a couple of mutations, structural analysis can help predict the clinical outcome of the disease.

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“…The R499H mutation causes loss of stabilization between domains I and II of the α-subunit without affecting the active site of the enzyme. 98 These patients progressed from having mild dysarthria to having anarthria in a mean time of 4.8 years. The most common symptoms at onset were speech problems and developmental delay.…”

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The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

et al. 2006

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OBJECTIVE-Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients.METHODS-A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, β-hexosaminidase enzyme activity, and mutation analysis was collected.RESULTS-In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression Address correspondence to Joe T. R. Clarke, MD, PhD, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. joe.clarke@sickkids.ca. The authors have indicated they have no financial relationships relevant to this article to disclose. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptto becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the TaySachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course.CONCLUSIONS-Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sa...

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Structural basis of the GM2 gangliosidosis B variant

Cited by 15 publications

References 27 publications

Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form

Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form

Structural study on mutant α-l-iduronidases: insight into mucopolysaccharidosis type I

The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

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