Screening for UBE3A gene mutations in a group of Angelman syndrome patients selected according to non-stringent clinical criteria

Abstract

The Angelman syndrome (AS) is caused by genetic abnormalities affecting the maternal copy of chromosome region 15q12. Until recently, the molecular diagnosis of AS relied on the detection of either a deletion at 15q11-13, a paternal uniparental disomy (UPD) for chromosome 15 or imprinting mutations. A fourth class of genetic defects underlying AS was recently described and consists of mutations of the UBE3A gene. The vast majority of mutations reported so far are predicted to cause major disruptions at the protein level. It is unclear whether mutations with less drastic consequences for the gene product could lead to milder forms of AS. We report on our results obtained by screening 101 clinically diagnosed AS patients for mutations in the UBE3A gene. Non-stringent clinical criteria were purposely applied for inclusion of AS patients in this study. The mutation search was carried out by single-strand conformation polymorphism (SSCP), and SSCP/restriction fragment length polymorphism (RFLP) analyses and revealed five novel UBE3A gene mutations as well as three different polymorphisms. All five mutations were detected in patients with typical features of AS and are predicted to cause frameshifts in four cases and the substitution of a highly conserved residue in the fifth. The results we obtained add to the as yet limited number of reports concerning UBE3A gene mutations. Important aspects that emerge from the data available to date is that the four classes of genetic defects known to underlie AS do not appear to cover all cases. The genetic defect underlying approximately 10% of AS cases, including some familial cases, remains unknown.

Investigation of UBE3A and MECP2 in Angelman syndrome (AS) and patients with features of AS

“…To determine whether the higher frequency of UBE3A mutations observed in familial compared to sporadic AS patients was statistically significant, we combined our data with those from the literature, and analyzed them using the χ 2 (2 × 2) contingency test. Data was collated from studies which report (i) strict clinical ascertainment, (ii) a thorough screen of the UBE3A gene in familial and sporadic cases of AS, and (iii) the total number of cases screened (Table II) [Malzac et al, 1998; Baumer et al, 1999; Fang et al, 1999; van den Ouweland et al, 1999]. Only cases meeting the clinical diagnostic criteria for AS were included.…”

“… The data from Malzac et al [1998], Fang et al [1999], van den Ouweland et al [1999], Baumer et al [1999], and our study were combined, and only included patients with a working diagnosis of AS. Cases of UBE3A mutations described by Kishino et al [1997] and Moncla et al [1999] were included in the study by Malzac et al [1998], and those originally reported by Matsuura et al [1997] and Tsai et al [1998] were included in Fang et al [1999], so there was no redundancy in numbers.…”

Distinct phenotypes distinguish the molecular classes of Angelman syndrome

“…12 54 57 Forty-five are unique mutations (fig 4), with no more than three unrelated subjects sharing a common error. Most defects are nonsense mutations that are predicted to result in premature termination during translation, and therefore may not represent true null mutations.…”

SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome

“…We had hoped that UBE3A transcripts might be subject to mRNA quality surveillance, because the QRT-PCR assay might then be an efficient method for the prescreening of "methylation-normal" AS patients. Such a prescreen would be welcome because the rate of detection of a UBE3A mutation in patients suspected of having AS is very low (see for example Malzac et al 1998;Baumer et al 1999;Fang et al 1999).…”