Researchers identify gene causing rare form of cleft palate

September 16, 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. (Refer to note 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 from 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 explains: "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 CXP 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.

For further information please contact:

Judith Moore
Press Office
Imperial College
Tel 44-20-7594-6702
Mobile 07803-886248

Victoria Taylor
Birth Defects Foundation
Tel 44-1785-255-146
Mobile 07818046792

Notes to editors

1. Title: X-linked cleft palate and ankyloglossia (CPX) is caused by mutations in the T-box transcription factor gene TBX22.

Journal: Nature Genetics Vol 29

Authors: Claire Braybrook,1 Kit Doudney,1 Ana Carolina B. Marçano, 2 Alfred Arnason,3 Arni Bjornsson,4 Michael A. Patton,5 Paul J. Goodfellow,6 Gudrun E. Moore1 and Philip Stanier1

1Institute of Reproductive and Developmental Biology, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
2Departamento de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, São Paulo, Brazil, P.O.Box 1501, 17043-900.
3The Bloodbank, 101 Reykjavik, Iceland. 4Department of Plastic Surgery, The University Hospital, 101 Reykjavik, Iceland

2. The sex-linked form of cleft palate is semi dominant on the female X chromosome. Females that 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) where the flap of skin under the tongue extend to the tip of the mouth. Male offspring from mothers that have the condition carry a 50 per cent change to inheriting cleft palate depending on which X chromosome they inherit from their mother.

3. Imperial College of Science, Technology and Medicine is an independent constituent part of the University of London. Founded in 1907, the College teaches a full range of science, engineering, medical and management disciplines at the highest level. The College is the largest applied science and technology university institution in the UK, with one of the largest annual turnovers (UKP339 million in 1999-2000) and research incomes (UKP176 million in 1999-2000).

Web site at

Imperial College London

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