Couple with baby

Imprinting disorders

24/6/03. By Richard Twyman

Some mutations have different effects depending on the parent from which they are inherited.

Most of our genes come in pairs, one copy inherited from each parent. In many cases the maternal and paternal alleles of the gene appear equally important. However, certain chromosome mutations cause very different diseases depending on which chromosome - the maternal or paternal copy - is affected.

This phenomenon, known as parental imprinting, indicates that the alternative parental alleles of some genes are not equivalent. It appears that only one copy of the gene is ever expressed, and that copy always comes from the same parent.

Parental imprinting can be seen in two disorders known as Prader-Willi syndrome and Angelman syndrome, both of which occur most often due to deletions affecting the long arm of chromosome 15. Both disorders feature learning difficulties but otherwise the symptoms are completely different. Prader-Willi syndrome includes obesity, a short stature and underdeveloped genitals. In contrast, Angelman syndrome involves epilepsy, unsteady walking and an unusually happy disposition with frequent inappropriate laughter. How can two such dissimilar diseases be caused by the same mutation?

While most individuals with these diseases have chromosome deletions, about a quarter possess apparently normal chromosomes. However, further investigation shows evidence of uniparental disomy, an unusual situation in which both copies of chromosome 15 are inherited from one parent. Prader-Willi syndrome is caused by deletions affecting the paternal copy of chromosome 15 or the possession of two maternal copies. The assumption is that the disease reflects the loss of genes that are normally expressed only on the paternal copy of the chromosome. In contrast, Angelman syndrome is caused by deletions affecting the maternal copy of chromosome 15 or the possession of two paternal copies. This reflects the opposite situation - the loss of genes that are normally only expressed on the maternal copy of the chromosome.

In a small proportion of individuals with each disease, there are two intact copies of chromosome 15, one inherited from each parent as expected. Such individuals have mutations in the short stretches of DNA that control parental imprinting, therefore disrupting the imprinting mechanism itself. Experiments have shown that chemical modification of the DNA in these control regions occurs either in the sperm or the egg, but never in both, resulting in the selective silencing of one copy of the imprinted genes. There are several other imprinted regions in the human genome in addition to the one on chromosome 15.

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