Researchers led by Dr. Philip Stanier from Imperial College, London, 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.

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 1/1,500 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 requiring a wide range of pediatric expertise.

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

"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 influence from environmental factors, making it easier to identify the genetic basis for this disorder."

The sex-linked form of cleft palate is semi dominant on the female X chromosome. Females who carry an X chromosome with the mutation do not exhibit the full condition as the other X chromosome compensates for the lack of function.

Under these circumstances, the condition appears as tongue tie (ankyloglossia), in which the flap of skin under the tongue extends to the tip of the mouth.

Male offspring from mothers who have the condition carry a 50 per cent chance of inheriting cleft palate, depending on which X chromosome they inherit from their mother.

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 explained.

"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 center to investigate reproduction, fetal development and neonatology, with a major emphasis on intracellular signaling and gene expression.

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

(Reference: X-linked cleft palate and ankyloglossia (CPX) is caused by mutations in the T-box transcription factor gene TBX22. Nature Genetics Vol 29.)

[Contact: Judith Moore, Victoria Taylor ]

17-Sep-2001