H19

The H19 gene provides instructions for making a molecule called a noncoding RNA. (RNA is a chemical cousin of DNA.) Unlike many genes, the H19 gene does not contain instructions for making a protein. The function of the gene is unknown, but researchers believe that it may act as a tumor suppressor, keeping cells from growing and dividing too fast or in an uncontrolled way. This gene is highly active before birth and may play an important role in early development.

People inherit one copy of most genes from their mother and one copy from their father. Both copies are typically active, or "turned on," in cells. The H19 gene, however, is active only when it is inherited from a person's mother. This sort of parent-specific difference in gene activation is caused by a phenomenon called genomic imprinting.

H19 is part of a cluster of genes on the short (p) arm of chromosome 11 that undergo genomic imprinting. Another gene in this cluster, IGF2, is also involved in growth and development. A nearby region of DNA known as imprinting center 1 (ICR1) or the H19 differentially methylated region (H19 DMR) controls the parent-specific genomic imprinting of both the H19 and IGF2 genes.

Beckwith-Wiedemann syndrome - associated with the H19 gene

Beckwith-Wiedemann syndrome often results from changes in a process called methylation that affects the ICR1 region. In genes that undergo genomic imprinting, the parent of origin is often marked, or "stamped," on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA.

In many people with Beckwith-Wiedemann syndrome, the ICR1 region has too many methyl groups attached (hypermethylation). Because the ICR1 region controls the genomic imprinting of the H19 and IGF2 genes, this abnormality disrupts the regulation of both genes. Specifically, hypermethylation of the ICR1 region leads to a loss of H19 gene activity and increased activity of the IGF2 gene in many tissues. A loss of H19 gene activity, which normally restrains growth, and an increase in IGF2 gene activity, which promotes growth, together lead to overgrowth and an increased risk of tumors in people with Beckwith-Wiedemann syndrome.

In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the ICR1 region. Like abnormal methylation, these deletions disrupt the activity of the H19 and IGF2 genes.

Russell-Silver syndrome - associated with the H19 gene

Changes in methylation of the ICR1 region are also responsible for some cases of Russell-Silver syndrome. The changes are different than those seen in Beckwith-Wiedemann syndrome and have the opposite effect on growth.

In Russell-Silver syndrome, the ICR1 region often has too few methyl groups attached (hypomethylation). Hypomethylation of the ICR1 region leads to a loss of IGF2 gene activity and increased activity of the H19 gene in many tissues. A loss of IGF2 gene activity, which normally promotes growth, and an increase in H19 gene activity, which restrains growth, together lead to poor growth and short stature in people with Russell-Silver syndrome.