INSTABILITY OF THE CGG REPEAT AND EXPRESSION OF THE FMR1 PROTEIN IN AMALE FRAGILE-X PATIENT WITH A LUNG-TUMOR

The molecular mechanism of the fragile X syndrome is based on the expa nsion of an CGG repeat in the 5' UTR of the FMR1 gene in the majority of fragile X patients. This repeat displays instability both between i ndividuals and within an individual. We studied the instability of the CGG repeat and the expression of the FMR1 protein (FMRP) in several d ifferent tissues derived from a male fragile X patient. Using Southern blot analysis, only a full mutation is detected in 9 of the 11 tissue s tested. The lung tumor contains a methylated premutation of 160 repe ats, whereas in the testis, besides the full mutation, a premutation o f 60 CGG repeats is detected. Immunohistochemistry of the testis revea led expression of FMR1 in the spermatogonia only, confirming the previ ous finding that, in the sperm cells of fragile X patients with a full mutation in their blood cells, only a premutation is present. Immunoh istochemistry of brain and lung tissue revealed that 1% of the cells a re expressing the FMRP. PCR analysis demonstrated the presence of a pr emutation of 160 repeats in these FMR1-expressing cells. This indicate s that the tumor was derived from a lung cell containing a premutation . Remarkably, despite the methylation of the EagI and BssHII sites, FM RP expression is detected in the tumor. Methylation of both restrictio n sites has thus far resulted in a 100% correlation with the lack of F MR1 expression, but the results found in the tumor suggest that the Cp Gs in these restriction sites are not essential for regulation of FMR1 expression. This indicates a need for a more accurate study of the ex act promoter of FMR1.