Cell Proliferation Alteration Linked to Cleft Palate

X-linked gene inactivation with 'mosaic' cells results in more severe anomalies in females

FRIDAY, Sept. 17 (HealthDay News) -- A previously discovered mutation in a gene implicated in the formation of cleft palate and other craniofacial abnormalities -- ephrin-B1 -- contributes to these abnormalities by controlling cell proliferation, and heterozygous genes are the cause of the more severe anomalies found in females, according to an animal study published in the Sept. 15 issue of Genes & Development.

Jeffrey O. Bush, Ph.D., and Philippe Soriano, Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle, conducted a mouse embryo study to determine the molecular and developmental mechanisms by which mutations in ephrin-B1 lead to cleft palate and other craniofacial anomalies included in a group of anomalies known as craniofrontonasal syndrome (CFNS). A second objective of the study was to determine why heterozygous females with one normal copy of the ephrin-B1 gene are more severely malformed than males who have no normal copy of the gene.

The researchers discovered that, in the mouse model, ephrin-B1 plays an important role in palatal development by regulating cell proliferation in the anterior palatal shelf mesenchyme. The more severe CFNS abnormalities observed in female mice embryos heterozygous for this type of mutation appeared to occur because of X-linked gene inactivation causing the embryos to have a "mosaic" cell proliferation; this occurs as cell multiplication is disrupted in some areas while developing normally in others, which creates abnormal craniofacial development.

"Craniofacial anomalies are among the most common human birth defect. Our findings represent a critical step forward in understanding how cleft palate and other malformations develop, and will hopefully bring us closer to finding ways to prevent or treat these abnormalities," Bush said in a statement.

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