Abstract
BackgroundMore than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene) have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect.Case PresentationWe here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother. Despite carrying the same UBE3A mutation, the proband shows a more severe phenotype whereas his sister shows a milder phenotype presenting the typical AS features.ConclusionsWe hypothesized that the mutation Leu125Stop causes both severe and milder phenotypes. Potential mechanisms include: i) maybe the proband has an additional problem (genetic or environmental) besides the UBE3A mutation; ii) since the two siblings have different fathers, the UBE3A mutation is interacting with a different genetic variant in the proband that, by itself, does not cause problems but in combination with the UBE3A mutation causes the severe phenotype; iii) this UBE3A mutation alone can cause either typical AS or the severe clinical picture seen in the proband.
Highlights
More than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene) have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect.Case Presentation: We here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother
Kubota et al, (1997) [9] have developed a methylationspecific PCR assay for detection of the PWS and Angelman syndrome (AS) based on the methylation status of the CpG island within the SNRPN gene
The majority of mutations found within UBE3A gene are localized at the hect domain region, which includes the 3′region of the exon 9, extends through the exon–16
Summary
Kubota et al, (1997) [9] have developed a methylationspecific PCR assay for detection of the PWS and AS based on the methylation status of the CpG island within the SNRPN gene. Afterwards, the DNA sequencing of exon 9 showed a deletion of four nucleotides (TAAC) affecting codons 125 and 126 resulting in a frameshift mutation, which creates a premature stop codon at position 125, 1031-1034delTAAC (Leu125Stop) (Figure 4). We report here that in spite of carrying the same mutation, the proband shows a more severe phenotype as he is not able to walk and does not present some of the typical AS facial features as wide mouth with wide-spaced teeth, happy behavior, arm positions and movements. This result may be associated to the phenotypic variability observed between patients, due to the differential methylation pattern along the SNRPN analyzed region containing 21 CpG dinucleotides To test this hypothesis we performed the bisulfite sequencing analysis of the patients, their mother and a normal control (Additional file 1).
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