Two siblings suffering from Angelman Syndrome with a novel c.1146T>G mutation in UBE3A: A case report

Abstract

Angelman syndrome (AS) is an autosomal dominant neurodevelopmental genetic disease with maternal imprint, which is associated with the presence of the abnormal chromosome 15q11-q13, and the loss of maternal specific expression of ubiquitin-protein ligase E3A (UBE3A). The expression levels of UBE3A depend on the parental origin and exhibit tissue specificity. In normal brain tissues, the maternal UBE3A gene is actively expressed, whereas the paternal UBE3A gene is not. In total, ~85% of pediatric patients with AS present with epilepsy within their 3rd year of life. This condition is usually difficult to control with medical treatment. An 8-year-old female visited the Affiliated Hospital of Jining Medical University due to frequent epilepsy. Her clinical manifestations included specific facial features, moderate mental retardation and frequent seizures. It was interesting to note that her 15-year-old sister exhibited similar clinical manifestations to those of AS. The results of the electroencephalogram and the imaging examinations were also in line with the characteristics of AS. In order to further clarify the diagnosis, all the suspected genes in her sister and in their parents were sequenced. The multiplex ligation-dependent probe amplification project of the Angel/chubby and copy number variation (CNV) sequencing were assessed concomitantly to identify the pathogenic genes responsible for the development of AS. The latter occurs due to the missense mutation c.1146T>G, which results in asparagine replacement by lysine at position 382 (p.Asn382Lys) in exon 7. This amino acid change affects the normal expression of UBE3A; the mutation is a novel mutation, which, to the best of our knowledge, has not been previously reported. Relevant large fragments of mutations and methylation abnormalities were not found in the associated genes. The data further revealed absence of 25-bp repeat mutations at the shear mutation site of exon 1 of the small nuclear ribonucleoprotein polypeptide N gene in the subjects examined. No suspected CNV was found following analysis.

Keywords: Angelman Syndrome; mutations; pediatric epilepsy; ubiquitin-protein ligase E3A.

Figure 1

Tertiary structures of the mutated and wild-type UBE3A proteins predicted by raptorX. (A) Tertiary structure of the wild-type UBE3A protein. (B) Predicted tertiary structure of UBE3A exhibiting that asparagine replacement by lysine at position 382 (p.Asn382Lys). Differences were identified among the two tertiary structures. UBE3A, ubiquitin-protein ligase E3A.

Figure 2

Pedigree chart of the examined family. The Chinese family investigated consisted of five members: Ⅰ1, the grandmother, healthy; Ⅰ2, the grandfather, deceased (mutation status unknown); Ⅱ1, the mother, 41 years old, healthy; Ⅱ2, the father, 38 years old, healthy; Ⅲ1, the first daughter, 15 years old, with AS; Ⅲ2, the proband (arrow), 8 years old, with AS. AS, Angelman Syndrome.

Figure 3

Image-based examination of the proband at the age of 8 years old. (A) Positron emission tomography-MRI: No metabolic abnormalities were observed. (B) MAP-junction, (C) MAP-thickness and (D) MAP-extension: No obvious abnormalities were found. MAP, Magnetic resonance T2 mapping.

Figure 4

(A) PET and PET/CT of the proband indicated decreased metabolism of the bilateral temporal lobe, notably on the right, and (B) in both cerebellar hemispheres. (C) PET and PET/CT scans of the proband’s sister indicated reduced metabolism in the left temporal lobe and (D) diffuse reduction of metabolism in the bilateral cerebellum. PET, positron emission tomography; CT, co-axial tomography.

Figure 5

Electroencephalogram of proband: (A) More frequent full lead 2.5-3.5 Hz sharp slow wave or slow wave rhythmic release, sometimes 4-6 Hz after the head rhythm, (B) Generalized tonic-clonic seizure. (C) Atypical absence seizure.

Figure 6

Electroencephalogram of the proband’s sister. In the bilateral frontal region, a 2.5-3.5 Hz medium and high amplitude cusp slow composite wave or slow wave rhythmic release was more frequently observed.

Figure 7

Electroencephalogram of the proband’s sister Ankylosing-atypical absence seizures complicated with Myoclonic seizures.

Figure 8

Genotype of the family members. The proband and first daughter had Angelman Syndrome. The mother, grandmother and father were healthy. No abnormalities were found in copy number variations. WT, wild-type.

Figure 9

Gene test results: c.1146T>G mutation identified in exon 15 of the UBE3A gene. c.1146T>G mutation in the (A) proband, (B) the mother and (C) the sister. Neither the (D) father nor (E) the grandmother had the mutation..c.1146T>G indicates a lysine residue being replaced with an asparagine residue at position 382 (p.Asn382Lys). Genomic coordinates, chr15:25616184.