Molecular genetics of Tay‐Sachs disease in Japan

Tanaka, Akemi; Sakazaki, Hisanori; Murakami, Hiroaki; Isshiki, Gen; Suzuki, Kazuyuki

doi:10.1007/bf00711597

Cited by 20 publications

(9 citation statements)

References 21 publications

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“…The formation of a disulfide bond between C420 and C458 could cause a much larger structural change. Expression analysis was also performed on the C458Y mutation, and the mutant cDNA did not express any catalytic activity of Hex A (Tanaka et al 1994). The results of Western blotting analysis of cell homogenates from cases 2 and 3 showed that the amount of mature asubunit was decreased in both cases (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

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Structural basis of the GM2 gangliosidosis B variant

et al. 2003

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To study the structural basis of the GM2 gangliosidosis B variant, we constructed the threedimensional structures of the human b-hexosaminidase a-subunit and the heterodimer of the a-and b-subunits, Hex A, by homology modeling. The a-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with the wild type to determine structural defects. These nine mutations were divided into five groups according to structural defects. R178H is deduced to affect the active site directly, because R178 is important for binding to the substrate. C458Y and W420C are predicted to cause drastic structural changes in the barrel structure carrying the active site pocket. R504C/H is deduced to introduce a disruption of an essential binding with D494 in the bsubunit for dimerization. R499C/H, located in an extrahelix, is deduced to disrupt hydrogen bonds with domain I and the barrel. R170W and L484P are deduced to affect the interface between domains I and II, causing destabilization. The structural defects reflect the biochemical abnormalities of the disease.

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Section: Discussionmentioning

confidence: 99%

“…As for the L484P mutation, an expression study was performed, but the mutant cDNA did not produce any Hex A activity (Tanaka et al 1994). The structural change caused by L484P was smaller than that by R170W (data not shown), but introducing P into the ahelix is deduced to destabilize the structure of the a-helix adjacent to domain I.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of the GM2 gangliosidosis B variant

et al. 2003

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“…We have earlier reported a mutation, IVS 5, Ϫ1G AE T, accounting for 80% of the mutant alleles among Japanese patients with Tay-Sachs disease, to be the major mutation in Japan (Tanaka et al 1993). The five additional disease-causing mutations that we reported subsequently were all limited to single alleles in 28 unrelated patients (Tanaka et al 1994). In this report, we describe two novel mutations and one additional mutation in the α subunit gene, one of which is the second most common mutation in Japanese patients.…”

Section: Introductionmentioning

confidence: 67%

Novel mutations, including the second most common in Japan, in the β-hexosaminidase α subunit gene, and a simple screening of Japanese patients with Tay-Sachs disease

et al. 1999

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Two novel mutations of the -hexosaminidase α subunit gene were identified in Japanese patients with the infantile form of Tay-Sachs disease. One mutation was a one-base deletion at nt613C, which generated a stop codon at two codons downstream, in three unrelated patients. The other mutation was a one-base substitution of G-to-A at IVS 5, ϩ1, which caused a splicing abnormality, in one patient. A missense mutation of R170W, which has already been reported in other ethnic groups, was also newly identified in one patient. In 1993, the most common mutation (IVS 5, Ϫ1G AE T) in Japanese patients with Tay-Sachs disease was reported as the major mutation in Japan accounting for 80% of 56 mutant alleles from 28 unrelated patients. The deletion of nt613C was the second most common mutation, accounting for 5% of the mutant alleles. The previously reported mutation IVS 5, Ϫ1G AE T and the nt613C deletion found in this study together accounted for 85% of the mutations causing Tay-Sachs disease among Japanese. Since these two mutations were located in or close to exon 6 and since they abolish Fok I (IVS 5, Ϫ1G AE T) and Sfa NI (nt613C deletion) restriction sites, respectively, they were screened rapidly by single polymerase chain reaction followed by digestion with these enzymes.

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“…Eight mutations were identified for 8 patients , which were five missense mutations, two splice-site mutations, and one two-base deletion. Five, R252L (CGT fi CTT), N295S (AAT fi AAC), W420C (TGG fi TGT), IVS 13, +2A fi C, and del 265- Tanaka et al (1994) b Mutation originally reported by Tanaka et al (1993) c The same mutation was previously reported by Mules et al (1992) and Akli et al (1993) d The same mutation was previously reported by Paw et al (1990), Triggs-Raine et al (1991), and Akli et al (1993) e The same mutation was previously reported by Akli et al (1993) 266AC (exon 2), were novel mutations responsible for infantile acute form of GM2 gangliosidosis.…”

Section: Resultsmentioning

confidence: 99%

“…Most patients show infantile acute clinical phenotype and have the same mutation of IVS 5, -1G fi T, which is considered to originate in Japan (Tanaka et al, 1994). Moreover, patients with milder forms have not been reported so far in the Japanese population.…”

Section: Discussionmentioning

confidence: 99%

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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Molecular genetics of Tay‐Sachs disease in Japan

Cited by 20 publications

References 21 publications

Structural basis of the GM2 gangliosidosis B variant

Structural basis of the GM2 gangliosidosis B variant

Novel mutations, including the second most common in Japan, in the β-hexosaminidase α subunit gene, and a simple screening of Japanese patients with Tay-Sachs disease

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

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