UBE3A and Imprinting
UBE3A is known to be “imprinted” in brain neurons [1]. This means that UBE3A gene from the paternally-derived chromosome 15 is almost completely inactive in many brain regions while the maternally-derived chromosome 15 gene is normally active. The brain neurons are normal even though they only have one active copy of the UBE3A gene. That chromosome deletions in AS occur only on the maternally-derived chromosome 15 indicate that UBE3A is active only on this chromosome, hence the deletion removes the only active copy of the gene. Disruptions of genes that are active on the paternally-derived chromosome 15 cause another developmental disorder, the Prader-Willi syndrome (PWS). PWS also involves imprinted gene(s) that are located close to but distinct from UBE3A. AS and PWS are quite unique because almost all other genetic disorders do not exhibit this type of imprinting effect.
The term “imprinting inheritance” can be difficult to understand. In order for an imprinted gene to be normally inherited and active on the correct parentally-derived chromosome (e.g., as occurs in normal individuals), there must be a mechanism for reversing the expression of genes at certain times of egg and embryo development. For example, when a normal father produces sperm, regardless of whether the sperm end up having the maternally or paternally derived 15, all must now be “stamped” or “imprinted” so that their UBE3A genes will be turned off. The opposite occurs in the normal mother, whose eggs must have all their UBE3A genes turned on. Imprinted genes are thus capable of having their activity instructions erased and re-stamped.
The pedigree illustrates how imprinting inheritance can cause recurrence of AS in somewhat distantly related relatives. When a UBE3A mutation is inherited in a family, individuals who inherit the mutation may get AS but others can be normal! Inheritance of a UBE3A mutation from the father (top left of pedigree) has no detectable effect on his immediate children since he passed on an inactive UBE3A gene. It does not matter if this gene has a mutation since each of his immediate children also inherited a normal chromosome 15 (e.g., normal UBE3A gene) from their mother. However, should his carrier daughter transmit the UBE3A mutation to any child, it will have AS since that child would also get an inactivated UBE3A from her father so now there is essentially no UBE3A activity present. The same type of inheritance pattern can also be seen in some families with Imprinting Center defects. Refer to Genetic Counseling for more information.
Fortunately, most individuals with AS will have acquired their condition through a non-inherited, spontaneous mutation. This is the situation in almost all cases of the large common deletion and thus imprinting inheritance in not observed.
1. Yamasaki K, Joh K, Ohta T, et al. Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Hum Mol Genet, 2003. 12(8): p. 837-47.