Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, speech impairment, ataxia, and happy disposition with frequent smiling. AS results from the loss of expression of a maternal imprinted gene, UBE3A, mapped within 15q11-q13 region, due to different mechanisms: maternal deletion, paternal UPD, imprinting center mutation, and UBE3A mutation. Deletion AS patients may exhibit hypopigmentation of skin, eye, and hair correlating with deletion of P gene localized in the distal part of Prader-Willi (PWS)/AS region. Our patient presented developmental delay, severe mental retardation, absence of speech, outbursts of laughter, microcephaly, ataxia, hyperactivity, seizures, white skin, no retinal pigmentation, and gold yellow hair. His parents were of African ancestry. The SNURF-SNRPN methylation analysis confirmed AS diagnosis and microsatellite studies disclosed deletion with breakpoints in BP2 and BP3. All of the 25 exons and flanking introns of the P gene of the patient, his father, and mother were investigated. The patient is hemizygous for the deleted exon 7 of the P gene derived from his father who is a carrier of the deleted allele. Our patient manifests OCA2 associated with AS due to the loss of the maternal chromosome 15 with the normal P allele, and the paternal deletion in the P gene. As various degrees of hypopigmentation are associated with PWS and AS patients, the study of the P gene in a hemizygous state could contribute to the understanding of its effect on human pigmentation during development and to disclose the presence of modifier pigmentation gene(s) in the PWS/AS region.

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

“…23 OCA2, an autosomal recessive gene that is responsible for type 2 oculocutaneous albinism, is currently attributed toward the hypopigmentation phenotype seen in type I (deletion) AS patients as it lies within the AS deletion region along 15q11-q13. 24,25 However, this does not explain why other AS patients with UBE3A mutations, imprinting defect along 15q11-q13 or paternal uniparental disomy (type II-IV), which have intact OCA2, still show to a certain extent, the hypopigmentation phenotype. 26 Gene expression in AS mouse cerebellum used in this study may be different from gene expression in other tissues such as the skin, even though neurons and skin are derived from the same lineage cells.…”

Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf–Hirschhorn syndrome

“…This mechanism was demonstrated in patients with Angelman/Prader Willi syndrome with a deletion in the 15q11 -q13 region, in combination with oculocutaneous albinism related to hemizygous mutations in the P gene. 26,27 In addition, unmasking a recessive deafness allele in the MYO15A is associated with sensorineural deafness in a patient with Smith -Magenis syndrome carrying the common 17p11.2 deletion. 28 Here, we demonstrate for the first time that a similar combination of a deletion and a recessive mutation may explain complex phenotypes of certain patients with WHS or WFS.…”

Clinical and genetic aspects of Angelman syndrome

“…In some children with AS, this hypopigmentation can be so severe that a form of albinism is suspected. 34,35 When AS is caused by the other genetic mechanisms, normal skin and eye pigmentation is seen. Not all AS children with deletions of the OCA2 gene are obviously hypopigmented but may only have relatively lighter skin color than either parent.…”