Missing cluster of RNAs implicated in Prader-Willi syndrome

By Ruth SoRelle, M.P.H.

Prader-Willi syndrome is a puzzling disorder. Children born with it are lethargic in the womb, are born with poor muscle tone and, ironically, have difficulty feeding as infants. They are short with small hands and feet and have developmental delay.

As children, most develop gross obesity because of insatiable hunger. If their weight is not controlled, they become diabetic.

Deleted gene cluster

Now, researchers at Baylor College of Medicine have identified a genetic cluster known as small nucleolar RNAs on chromosome 15 that is inherited from the father as the source of the disorder. When this cluster is deleted, the children develop Prader-Willi, said Arthur Beaudet, M.D., chair of molecular and human genetics at BCM and senior author of a report in a recent issue of Nature Genetics.

Best evidence

"There has been a longstanding debate as to which gene or genes are responsible for Prader-Willi syndrome. These results provide the strongest evidence yet as to the identity of the Prader-Willi gene(s)," said Beaudet. "Deficiency of the genes of the HBII-85 snoRNA cluster (the small nucleolar RNAs) causes the major features of Prader-Willi syndrome."

"Prader-Willi syndrome is the first disorder known to be associated with the loss of these small nucleolar RNAs," said Beaudet.

The finding marks a departure from the best known role of RNAs, serving as the template for making protein. Instead, they guide chemical modifications of many cellular RNAs with diverse functions, and even possibly messenger RNAs, which are the decoders of the genetic message that results in the production of proteins. Proteins are the workhorses of cell, carrying out most of its functions.

A child's genome

In a study involving the genome of a child with Prader-Willi syndrome, Beaudet and his colleagues found that a deletion of genetic material for a particular cluster of these small nucleolar RNAs called HBII-85 was associated with many of the symptoms attributed to Prader-Willi syndrome in this child.

Studies in mice by other investigators also suggested that the loss of these particular forms of RNA contributed to the problems associated with the disease, said Beaudet and his colleagues.

Now an answer

In an accompanying review of the research, Dr. Jo Peters of the Medical Research Council in Oxfordshire, United Kingdom, wrote, "Both the genetics and the phenotype (visible symptoms) of PWS (Prader-Willi syndrome) are complex, and identifying the gene(s) responsible has been a challenge, but we now have the answer."

Others who took part in this research include Trilochan Sahoo, Daniela del Gaudio, Jennifer R German, Marwan Shinawi, Sarika U. Peters, Richard E. Person and Sau Wai Cheung, all of BCM, and Adolfo Garnica of St. Francis Hospital in Tulsa, Okla.

Funding for this research came from the National Institutes of Health, the Mental Retardation and Developmental Disabilities Research Center and the Rare Disease Clinical Research Consortia.

The article is available in Nature at http://www.nature.com/ng/journal/v40/n6/pdf/ng.158.pdf.