Chronic GM2 gangliosidosis type Sandhoff associated with a novel missense HEXB gene mutation causing a double pathogenic effect

Santoro, Massimo; Modoni, Anna; Sabatelli, Mario; Madia, Francesca; Piemonte, Fiorella; Tozzi, Giulia; Ricci, Enzo; Tonali, P.; Silvestri, Gabriella

doi:10.1016/j.ymgme.2006.12.004

Cited by 14 publications

(11 citation statements)

References 25 publications

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“…The variant was identified experimentally and subsequently predicted to cause the loss of two ESEfinder sites [41]. Our analysis using NI-ESRs revealed that this mutation caused the loss of five overlapping ESEs and the creation of two overlapping ESSs (both of which were direct conversions from ESEs to ESSs).…”

Section: Discussionmentioning

confidence: 84%

Genomic features defining exonic variants that modulate splicing

2010

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Section: Discussionmentioning

confidence: 84%

Genomic features defining exonic variants that modulate splicing

2010

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“…triplets also causes aberrant splicing [Cogan et al, 1997;Dobrowolski et al, 2010;Llewellyn et al, 1996;Matern et al, 2003;Santoro et al, 2007]. We have previously shown that disruption of the preexisting GGG triplet by a G>C substitution can correct splicing from the mutant sequence of PAH and HEXB [Dobrowolski et al, 2010], whereas McCarthy and Phillips (1998) have shown this for the GH1 gene GGG triplets.…”

Section: Discussionmentioning

confidence: 99%

“…We suggest that also in these cases the disease‐causing variation apparently has a dual negative effect by simultaneously creating or increasing the score for the hnRNP A1 and hnRNP A2/B1 motif, CAGGGU or UAGGGA, and at the same time creating a DGGGD or triple GGG motif for hnRNP H. In addition, the simultaneous presence of a second flanking GGG triplet most probably contributes further by serving as a hnRNP H‐binding site. There are several examples of published single‐nucleotide variations that create this kind of closely spaced GGG triplets and cause aberrant splicing even without the simultaneous creation of hnRNP A1 or hnRNP A2/B1 motifs, indicating that isolated creation of GGG triplets also causes aberrant splicing [Cogan et al., ; Dobrowolski et al., ; Llewellyn et al., ; Matern et al., ; Santoro et al., ]. We have previously shown that disruption of the preexisting GGG triplet by a G>C substitution can correct splicing from the mutant sequence of PAH and HEXB [Dobrowolski et al., ], whereas McCarthy and Phillips () have shown this for the GH1 gene GGG triplets.…”

Section: Discussionmentioning

confidence: 99%

“…(GGG), the presence of an inhibitory GGG triplet in the 5 splice site sequence. The genes listed are APC, adenomatosis polyposis coli [Gonçalves et al, 2009]; PAH, phenylalanine hydroxylase [Dobrowolski et al, 2010]; CHRNA1, cholinergic receptor, nicotinic, alpha 1 [Dobrowolski et al, 2010;Masuda et al, 2008]; HSD17B10, hydroxysteroid (17-beta) dehydrogenase 10 [Lenski et al, 2007]; ACADSB, short/branched chain acyl-CoA dehydrogenase [Dobrowolski et al, 2010;Matern et al, 2003]; HEXB, hexosaminidase B (beta polypeptide) [Dobrowolski et al, 2010;Santoro et al, 2007]; and HMBS, hydroxymethylbilane synthase [Llewellyn et al, 1996].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that disruption of the preexisting GGG triplet by a G>C substitution can correct splicing from the mutant sequence of PAH and HEXB [Dobrowolski et al, 2010], whereas McCarthy and Phillips (1998) have shown this for the GH1 gene GGG triplets. In Figure 5, we have aligned sequences exemplifying this mechanism, including examples from the HEXB gene [Santoro et al, 2007], the HMBS gene [Llewellyn et al, 1996], and the ACADSB gene [Matern et al, 2003].…”

Section: Discussionmentioning

confidence: 99%

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TheETFDHc.158A>G Variation Disrupts the Balanced Interplay of ESE- and ESS-Binding Proteins thereby Causing Missplicing and Multiple Acyl-CoA Dehydrogenation Deficiency

et al. 2013

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Multiple acyl-CoA dehydrogenation deficiency is a disorder of fatty acid and amino acid oxidation caused by defects of electron transfer flavoprotein (ETF) or its dehydrogenase (ETFDH). A clear relationship between genotype and phenotype makes genotyping of patients important not only diagnostically but also for prognosis and for assessment of treatment. In the present study, we show that a predicted benign ETFDH missense variation (c.158A>G/p.Lys53Arg) in exon 2 causes exon skipping and degradation of ETFDH protein in patient samples. Using splicing reporter minigenes and RNA pull-down of nuclear proteins, we show that the c.158A>G variation increases the strength of a preexisting exonic splicing silencer (ESS) motif UAGGGA. This ESS motif binds splice inhibitory hnRNP A1, hnRNP A2/B1, and hnRNP H proteins. Binding of these inhibitory proteins prevents binding of the positive splicing regulatory SRSF1 and SRSF5 proteins to nearby and overlapping exonic splicing enhancer elements and this causes exon skipping. We further suggest that binding of hnRNP proteins to UAGGGA is increased by triggering synergistic hnRNP H binding to GGG triplets located upstream and downsteam of the UAGGGA motif. A number of disease-causing exonic elements that induce exon skipping in other genes have a similar architecture as the one in ETFDH exon 2.

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Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles

et al. 2008

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We report the molecular characterization of 12 unrelated Italian patients affected with Sandhoff disease (SD), a recessively inherited disorder caused by mutations in HEXB gene. We identified 11 different mutations of which six are novel: one large deletion of 2,406 nt, (c.299+1471_408del2406), one frameshift mutation c.965delT (p.I322fsX32), one nonsense c.1372C>T (p.Q458X), and three splicing mutations (c.299G>T, c.300-2A>G and c.512-1G>T). One allele was only characterized at the messenger RNA (mRNA) level (r = 1170_1242del). Real-time polymerase chain reaction analysis of the HEXB mRNA from fibroblasts derived from patients carrying the novel point mutations showed that the presence of the premature termination codon in the transcript bearing the mutation c.965delT triggers the nonsense-mediated decay (NMD) pathway, which results in the degradation of the aberrant mRNA. The presence of the c.299G>T mutation leads to the degradation of the mutated mRNA by a mechanism other than NMD, while mutations c.300-2A>G and c.512-1G>T cause the expression of aberrant transcripts. In our group, the most frequent mutation was c.850C>T (p.R284X) representing 29% of the alleles. Haplotype analysis suggested that this mutation did not originate from a single genetic event. Interestingly, the common 16-kb deletion mutation was absent. This work provides valuable information regarding the molecular genetics of SD in Italy and provides new insights into the molecular basis of the disease.

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Chronic GM2 gangliosidosis type Sandhoff associated with a novel missense HEXB gene mutation causing a double pathogenic effect

Cited by 14 publications

References 25 publications

Genomic features defining exonic variants that modulate splicing

Genomic features defining exonic variants that modulate splicing

TheETFDHc.158A>G Variation Disrupts the Balanced Interplay of ESE- and ESS-Binding Proteins thereby Causing Missplicing and Multiple Acyl-CoA Dehydrogenation Deficiency

Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles

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