engleski

A two-hit model for developmental defects in Gorlin syndrome

Many birth defects that are rare the general population cluster in families. A two-hit mechanism, similar to Knudson's model for neoplasia, could explain both sporadic and familial anomalies, but molecular evidence is lacking. Gorlin syndrome is an autosomal dominant disorder characterized by both cancer predisposition and a variety of malformations including pits of the palms and soles, bifid ribs, spina bifida occulta and keratocysts of the jaw. The gene maps to chromosome 9q22 and probably functions as a tumour suppressor based on deletion of this region in many neoplasms related to the syndrome. Some of the associated developmental defects might also arise through a two-hit mechanism. Like neoplasms in cancer predisposition syndromes, the jaw cysts in Gorlin syndrome are multiple and appear in a random pattern, but similar isolated defects are seen occasionally in the general population. They might result from homozygous inactivation of the Gorlin syndrome gene in an early progenitor cell of the relevant tissue. We have examined a series of chromosome 9 polymorphisms in jaw cysts and matched constitutional tissue and found that the cyst lining loses the normal copy of the Gorlin syndrome region while retaining the mutant copy. These results suggest that a somatic mutation of a relevant gene in an embryonic or fetal cell leads to abnormal migration or differentiation or perhaps failure to undergo programmed cell death, manifested later as a developmental defect.

two-hit model ; developmental defects ; Gorlin syndrome ; LOH

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