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Researchers identify gene causing rare form of cleft palate

September 14, 2001

The identification of a gene that causes a rare form of the congenital defect, cleft palate, may offer an important insight into human development and the mechanisms involved in the condition.

Researchers led by Dr Philip Stanier from Imperial College have found that the sex-linked form of cleft palate (CPX) and an associated form of the disorder known as tongue-tie are caused by mutations in a gene called T-box 22. (See notes to editors)

The study published online today in the journal Nature Genetics follows extensive genetic analysis of family pedigrees from diverse ethnic backgrounds over the past 14 years.

Dr Philip Stanier of the Institute of Reproductive and Developmental Biology at Imperial College's Hammersmith campus, said:

"This discovery enables us to investigate the role of a major genetic determinant required for normal palate formation and to identify other mutations that may also play roles in more common forms of the disorder."

Cleft palate is a birth defect affecting 1/1500 births as a result of malformation of the palate during key stages of pregnancy. Children born with the condition have problems with feeding, speech, hearing and psychological development and require corrective surgery involving a wide range of paediatric expertises.

"Despite the high prevalence of cleft palate little is known about the underlying causes," Dr Stanier explained.

"In part, this is because most clefts arise through the disturbance to a complex but poorly understood balance between genes and the environment. The sex-linked form of cleft palate, CPX, has minimal influences from environmental factors making is easier to identify the genetic basis for this disorder."

Using data collected from Icelandic, Brazilian, Canadian and Native American families the genetic technique of positional cloning was used to identify the region on the chromosome where the gene for CPX might be (Nature 1987: 326, 91-92). Recent advances in molecular techniques enabled researchers to sequence the region and using information from the Human Genome Project candidate genes were identified.

Three possible genes, previously not implicated in human disease, were found and compared with gene sequences from family pedigrees. A number of different mutations were identified in the gene T-box 22 which, scientists say, would cause catastrophic effects to the gene and protein products.

"The T-box 22 gene gives rise to a type of protein known as a transcription factor. Transcription factors serve to regulate the activity of other genes that need to function at key stages of embryological development and play essential roles in formation of the embryo," Dr Stanier said.

"In the long term, identification of the targets for the T-box 22 protein may offer hope for a prenatal therapeutic intervention for cleft palate." he added.

The Institute of Reproductive and Developmental Biology, based at the Wolfson and Weston Research Centre for Family Health, was formed in the spring of 2001 as a multidisciplinary research centre to investigate reproduction, fetal development and neonatology with a major emphasis on intracellular signalling and gene expression.

The programme of research has been supported by the Birth Defects Foundation, the Dunhill Medical Trust, the Medical Research Council and the Hayward Foundation.

Imperial College, University of London