A Novel UBE3A Truncating Mutation in Large Tunisian Angelman Syndrome Pedigree

Faculté de Médecine de Tunis, Laboratoire de Génétique Humaine, Tunis, Tunisia.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 01/2010; 152A(1):141-6. DOI: 10.1002/ajmg.a.33179
Source: PubMed


We identified in a large Tunisian pedigree a novel UBE3A frameshift mutation in exon 16 coding region, and we expect that the resulting UBE3A truncated protein in our patients is non-functional since the mutation implies the catalytic region of the enzyme. The family includes 14 affected patients born from four sisters. This mutation was found in all surviving affected individuals and their mothers pointing out the importance of genetic counseling possibility in Angelman syndrome (AS). All patients had severe mental retardation with epilepsy and microcephaly. Minor clinical expression variation was observed among the investigated patients. The severity of clinical expression is related to the detected molecular variation: deletion of 15 bp and insertion of 7 bp. These results are concordant with the gene expression observed in previously reported individuals with AS and truncated UBE3A protein.

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    • "The majority of UBE3A mutations found in AS are protein truncating mutations [Kishino et al., 1997; Matsuura et al., 1997; Malzac et al., 1998; Lossie et al., 2001]. More than 60 mutations have been reported and 60–70% of these involve small deletions and duplications leading to frameshift mutations [Abaied et al., 2009; Camprubi et al., 2009; Stenson et al., 2009]. Another approximate 25% involve missense and nonsense mutations with the remainder representing splicing defects, gross deletions and complex rearrangements [Stenson et al., 2009]. "
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    ABSTRACT: The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2-q13 genomic region identifies 75-80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5-10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.
    Preview · Article · Apr 2012 · Molecular syndromology
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    • "To date, four genetic mechanisms are known to be responsible for AS and include: (i) maternallyderived interstitial deletions (ca. 4 Mb) of 15q11- q13 (70-75% of cases); (ii) paternal uniparental disomy (UPD) of the whole chromosome 15 (2-5%); (iii) defects in the imprinting process (ICP) (3-5%); (iv) nucleotide substitutions as well as small insertion/deletions of the gene encoding E6AP-E3 ubiquitin protein ligase (UBE3A). All these abnormalities always involve a region of chromosome 15, comprising the UBE3A gene, suggesting that a dysfunctional or absent UBE3A protein is a major cause of AS (Kishino et al., 1997; Matsuura et al., 1997; Rougeulle et al., 1997; Abaied et al., 2010). Chromosomal, molecular and clinical data on AS patients have also been used to attempt a "
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    ABSTRACT: Angelman syndrome (AS) is a severe neurobehavioural disorder caused by failure of expression of the maternal copy of the imprinted domain located on 15q11-q13. There are different mechanisms leading to AS: maternal microdeletion, uniparental disomy, defects in a putative imprinting centre, mutations of the E3 ubiquitin protein ligase (UBE3A) gene. However, some of suspected cases of AS are still scored negative to all the latter mutations. Recently, it has been shown that a proportion of negative cases bear large deletions overlapping one or more exons of the UBE3A gene. These deletions are difficult to detect by conventional gene-scanning methods due to the masking effect by the non-deleted allele. In this study, we have used for the first time multiplex ligation-dependent probe amplification (MLPA) and comparative multiplex dosage analysis (CMDA) to search for large deletions affecting the UBE3A gene. Using this approach, we identified a novel causative deletion involving exon 8 in an affected sibling. Based on our results, we propose the use of MLPA as a fast, accurate and inexpensive test to detect large deletions in the UBE3A gene in a small but significant percentage of AS patients.
    Full-text · Article · Nov 2010 · Experimental and Molecular Medicine
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    ABSTRACT: Tunisia is one of the North African countries, geographically situated in a central position at the crossroad between Africa and Europe. The demographic features of the Tunisian population include among others high rates of consanguinity. We report, here on the spectrum of genetic diseases in Tunisia. The review of the literature, including other available information (gray literature) showed that there are at least 346 genetic disorders for which cases have been identified in the Tunisian population. Among these, 62.9% are autosomal recessive, 23% autosomal dominant, 5.4% X-linked, and the remaining are of Y-linked, mitochondrial, and unknown mode of transmission. Fifty percent of the reported conditions in this study are caused by at least one mutation. For autosomal recessive diseases, most of the mutations were identified at homozygous state among the affected individuals. Part of the mutations was the result of a founder effect; these are the consequences of the high rate of consanguinity. The congenital malformations, diseases of the nervous system and metabolic disorders are the major groups of genetic diseases affecting the Tunisian population. The large spectrum of diseases and their relatively high frequency could be explained by the high degree of inbreeding and the presence of multiple mutations, either allelic or in different genes. This is due to the richness of the genetic background of the studied population. A multidisciplinary approach is essential to develop adequate preventive programmes adapted to the social, cultural, and economic context. © 2010 Wiley-Liss, Inc.
    Full-text · Article · Jan 2011 · American Journal of Medical Genetics Part A
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