Angelman syndrome ... (Angelman syndrome) - Genes OCA2, Ube3a and chromosome 15

Angelman syndrome is a complex genetic process that primarily affects the nervous system. Characteristic features include developmental delay, intellectual disability, severe speech disturbances, and ataxia. In addition, most affected children have epilepsy and microcephaly. Other common features include unusually clear skin with light colored hair and scoliosis. The life expectancy of people affected seems to be almost normal.

Many of the characteristics of Angelman syndrome are due to loss of function of UBE3A, located on the long arm of chromosome 15 (15q11.2). This gene encodes ubiquitin ligase E3A the. It is believed that this protein plays a critical role in normal development and function of the nervous system. Normally, people inherit a copy of Ube3a gene from each parent. Both copies of the gene are active in many tissues. However, in certain areas of the brain it is active only the maternal copy. This specific gene activation is due to genomic imprinting. If the maternal copy of UBE3A is lost due to a chromosomal change or a mutation of a gene, the person will not have any active copy of the gene in some parts of the brain. This lack of functional enzyme would probably lead to the major signs and symptoms of Angelman syndrome. Several different genetic mechanisms can inactivate or remove the maternal copy of UBE3A. Most cases of Angelman, about 70%, occurs when a segment of the maternal chromosome 15 containing this gene is deleted. In other cases, about 11%, Angelman syndrome is due to a mutation in the maternal copy of UBE3A.

In a small percentage of cases, Angelman syndrome occurs when a person inherits two copies fathers instead of one copy from each parent, a phenomenon called paternal UPD. Rarely, Angelman syndrome may also be due to translocation, or a mutation or defect in the DNA region which controls the activation of UBE3A. These genetic changes can disable abnormally UBE3A or other genes in the maternal copy of chromosome 15.

In some people with Angelman syndrome, loss of a gene called OCA2, located in the long arm of chromosome 15 (15q), it is associated with light colored hair and fair skin. This gene, encoding the P protein, found in melanocytes. Although the exact function of the P protein is unknown, it is essential for normal pigmentation and is likely to be involved in the production of melanin. Within melanocytes, P protein can transport molecules inside and outside of melanosomes, melanin is produced where. In addition, it is believed that this protein contributes to regulate the pH of melanosomes.

The OCA2 is in the segment of chromosome 15 which is removed often in people with this syndrome. However, the loss of OCA2 gene is not responsible for the other signs and symptoms of Angelman syndrome. Cells with a single copy of the gene encoding OCA2 a reduced amount of P protein compared to cells with two functional copies of this gene, which affects the color of the skin and hair. A small percentage of people with Angelman syndrome also have oculocutaneous albinism type 2. This condition occurs when people have two functional copies of the gene in every cell OCA2. In addition to a deletion in chromosome 15, which removes a copy of OCA2, these individuals have a mutation in the OCA2 in the other copy of chromosome 15. As a result, cells encode functional protein little or no P. Deficiency or absence of proteins P interrupts the production of melanin, leading to the characteristic features of albinism.

The causes of Angelman syndrome are unknown in 10 to 15% of affected individuals. Changes involving other genes or chromosomes can be responsible for the process in these cases.

Most cases of Angelman not inherited, particularly those caused by a deletion on chromosome 15 maternal or paternal UPD. These genetic changes occur as random events during the formation of reproductive cells or early embryonic development. As a result, affected individuals often have no history of the disease in his family. Rarely, genetic change responsible for Angelman can be hereditary. For example, it is possible that a mutation in UBE3A or the nearby region of DNA that controls gene activation is transmitted from one generation to the next.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Angelman syndrome, by complete PCR amplification of exons and UBE3A OCA2 respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).