A common ? hexosaminidase gene mutation in adult Sandhoff disease patients

Gomez-Lira, Macarena; Sangalli, Antonella; Mottes, Monica; Perusi, Chiara; Pignatti, Pier Franco; Rizzuto, Nicolo’; Salviati, Alessandro

doi:10.1007/bf00191799

Cited by 31 publications

(21 citation statements)

References 23 publications

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“…However, using transfection experiments Wakamatsu et al showed that this variant actually causes the activation of a cryptic splice site which results in the loss of exon 11 from the processed transcript accounting for the loss of β-hexosaminidase activity [25]. Interestingly, this allele was observed once in each of the Finnish, Italian, and Japanese populations included in the 1000 Genomes sample which correlates well with the previous literature reports from Wakamatsu et al (Japanese patient) and Gomez-Lira et al (Italian patient) [25,28]. …”

Section: Resultssupporting

confidence: 86%

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Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis

Fitterer

Hall

Antonishyn

et al. 2014

Molecular Genetics and Metabolism

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Sandhoff disease is a rare progressive neurodegenerative genetic disorder with a high incidence among certain isolated communities and ethnic groups around the world. Previous reports have shown a high occurrence of Sandhoff disease in northern Saskatchewan. Newborn screening cards from northern Saskatchewan were retrospectively screened in order to investigate the incidence and determine the carrier frequency of Sandhoff disease in these communities. PCR-based screening was conducted for the c.115delG (p.(Val39fs)) variant in the HEXB gene that was previously found in 4 Sandhoff disease patients from this area. The carrier frequency for this allele was estimated to be ~1:27. MS/MS-based screening of hexosaminidase activity along with genetic sequencing allowed for the identification of additional variants based on low total hexosaminidase activity and high % hexosaminidase A activity relative to c.115delG carriers. In total 4 pathogenic variants were discovered in the population (c.115delG, c.619A>G, c.1601G>T, and c.1652G>A) of which two are previously unreported (c.1601G>T and c.1652G>A). The combined carrier frequency of these alleles in the study area was estimated at ~1:15. Based on the number of cases of Sandhoff disease from this area we estimate the incidence to be ~1:390 corresponding to a child being born with the disease every 1–2 years on average. The results from our study were then compared with variants in the HEXB gene from the genomes available from the 1000 Genomes project. A total of 19 HEXB variants were found in the 1092 genomes of which 5 are suspected of having a deleterious effect on hexosaminidase activity. The estimated carrier frequency of Sandhoff disease in Saskatchewan at 1:15 is more than 3 times higher than the carrier frequency in the global sample provided by the 1000 Genomes project at 1:57.

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Section: Resultssupporting

confidence: 86%

“…The c.1250C>T variant has been described by Wakamatsu et al and Gomez-Lira et al in compound heterozygous patients suffering from juvenile and adult onset Sandhoff disease respectively [25,28]. This variant results in the change of Pro at position 417 to Leu.…”

Section: Resultsmentioning

confidence: 99%

Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis

Fitterer

Hall

Antonishyn

et al. 2014

Molecular Genetics and Metabolism

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“…In G M2 gangliosidoses, the critical threshold of Hex A activity, inferred from the maximal activity of the respective enzyme in late-onset patients and the minimal activity of healthy probands, is $510% of the average activity (27). The P417L allele has been reported to be associated with a variety of late-onset phenotypes; a P417L mutation and a 16-kb deletion at the 5 0 -end were noted in a patient with the motor neuron disease phenotype (7). Both autonomic nervous system dysfunction and normal phenotype were observed in one family with the same combination of HEXB mutations (5).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, a variety of less severe and chronic phenotypes of Sandhoff disease with a small percentage of residual Hex A activity have been reported, including motor neuron disease, spinocerebellar ataxia, intellectual disability and dysfunction of the autonomic nervous system (210). Only four missense mutations (Y456S, P504S, R533H and P417L) associated with the adult form of Sandhoff disease presenting the motor neuron disease phenotype have been reported (3,7,9,1113). In this study, we report the molecular and biochemical study of a Japanese male patient with the adult form of Sandhoff disease with the motor neuron disease phenotype.…”

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confidence: 99%

Characterization of the mutant β-subunit of β-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype

Yamada

Takado

Kato

et al. 2012

The Journal of Biochemistry

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The adult form of Sandhoff disease with the motor neuron disease phenotype is a rare neurodegenerative disorder caused by mutations in HEXB encoding the b-subunit of b-hexosaminidase, yet the properties of mutant b-subunits of the disease have not been fully determined. We identified a novel mutation (H235Y) in the b-sheet of the (b/a) 8 -barrel domain, in addition to the previously reported P417L mutation that causes aberrant splicing, in a Japanese patient with the motor neuron disease phenotype. Enzyme assays, gel filtration studies and immunoprecipitation studies with HEK293 cells transiently expressing mutant b-subunits demonstrated that the H235Y mutation abolished both ab and bb dimer formation without increasing b-hexosaminidase activity, whereas other reported mutant b-subunits (Y456S, P504S or R533H) associated with the motor neuron disease phenotype formed dimers. Structural analysis suggested that the H235Y mutation in the b-sheet of the (b/ a) 8 -barrel domain changed the conformation of the b-subunit by causing a clash with the E288 side chain. In summary, H235Y is the first mutation in the b-sheet of the (b/a) 8 -barrel domain of the b-subunit that abolishes ab and bb dimer formation; the presented patient is the second patient to exhibit the motor neuron disease phenotype with P417L and a non-functional allele of HEXB.

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“…The initial history of the patient reported here has been previously described [10]. Briefly, he is a 53 year-old man who presented, at the age of 28, when he was a rock climber, with progressive difficulty in climbing and going down mountain paths and getting up from supine position.…”

Section: Case Reportmentioning

confidence: 99%

Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up

Scarpelli

Tomelleri

Bertolasi

et al. 2014

Molecular Genetics and Metabolism Reports

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An adult with Sandhoff disease presented with pure lower motor neuron phenotype. Twenty years later, he showed signs of upper motor neuron involvement. 25 years from the onset, his muscle weakness slightly worsened but he was fully independent in activities of daily living.GM2-gangliosidosis can manifest as a motor neuron disease with a slowly progressive course. The correct knowledge of the natural history can be really important to achieve the diagnosis, design new therapies and evaluate clinical trials.

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A common ? hexosaminidase gene mutation in adult Sandhoff disease patients

Cited by 31 publications

References 23 publications

Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis

Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis

Characterization of the mutant β-subunit of β-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype

Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up

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