FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome

The fragile X mental retardation 1 gene (FMR1) mutation is strongly correla ted with specific and marked neurobehavioral and neuroanatomical abnormalit ies. The protein product, FMRP, is highly expressed in neurons of the norma l mammalian brain, and absent or in low levels in leukoctyes from individua ls with fragile X (FraX)-associated mental impairment. Inferences which ari se from these findings are that FMRP has a critical role in the development and functioning of the brain, and that leukocyte-derived molecular assessm ents provide a good indicator of FMR1 expression in that organ. This latter conclusion appears true in most cases even though the typical FMR1 mutatio n is an unstable triplet repeat expansion which demonstrates somatic hetero geneity within and across tissues. Blood to brain correspondence in FraX pa tients has only rarely been confirmed by the direct study of human brain sp ecimens and, to our knowledge, it has never been studied in living individu als with the FMR1 mutation, Tn this report, we describe the FMR1 patterns i n olfactory neuroblasts (ON) from two living brothers with expansion mutati ons in their leukocytes who are mentally retarded and autistic, ON were cho sen for study because they are accessible neurons closely linked to the bra in. In both subjects, the ON genotype was highly, but not perfectly, consis tent with that observed in leukocytes, Protein phenotypes across tissues we re completely consistent showing the absence of FMRP-immunoreactivity (-ir) , These results augment the limited amount of direct evidence which indicat es that FMR1 mutation patterns in leukocytes are a good, albeit potentially fallible, reflection of such patterns in the brain, This report further de monstrates the feasibility of using ON samples to evaluate the FMR1 mutatio n in humans in vivo. (C) 1999 Wiley-Liss, Inc.