Is the gene for von Recklinghausen neurofibromatosis somatically unstable?

Abstract

The yellow-nonyellow pattern of the tortoiseshell guinea pig is presented as a model for the distribution of mutant and nonmutant neural-crest cells in von Recklinghausen neurofibromatosis (NF-1). The following hypotheses are offered to explain the developmental genetics of the variable phenotype. (1) The gene for NF-1 is somatically unstable; reverse somatic mutation occurs at a high frequency among the stem cells of clones of neural-crest cells in all affected individuals. (2) The normal reverted cells suppress the proliferation of residual mutant cells when both types are in close proximity. (3) At puberty, proliferation of normal cells decelerates, but proliferation in islands of residual mutant cells accelerates and results in the development of neurofibromas. (4) Plexiform neurofibromas occur when reverse mutation fails to occur or takes place relatively late within a large clonal population of mutant cells.