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

Abstract

The fragile X mental retardation 1 gene (FMR1) mutation is strongly correlated with specific and marked neurobehavioral and neuroanatomical abnormalities. The protein product, FMRP, is highly expressed in neurons of the normal mammalian brain, and absent or in low levels in leukocytes from individuals with fragile X (FraX)-associated mental impairment. Inferences which arise from these findings are that FMRP has a critical role in the development and functioning of the brain, and that leukocyte-derived molecular assessments provide a good indicator of FMR1 expression in that organ. This latter conclusion appears true in most cases even though the typical FMR1 mutation is an unstable triplet repeat expansion which demonstrates somatic heterogeneity within and across tissues. Blood to brain correspondence in FraX patients has only rarely been confirmed by the direct study of human brain specimens and, to our knowledge, it has never been studied in living individuals with the FMR1 mutation. In this report, we describe the FMR1 patterns in olfactory neuroblasts (ON) from two living brothers with expansion mutations in their leukocytes who are mentally retarded and autistic. ON were chosen for study because they are accessible neurons closely linked to the brain. In both subjects, the ON genotype was highly, but not perfectly, consistent with that observed in leukocytes. Protein phenotypes across tissues were completely consistent showing the absence of FMRP-immunoreactivity (-ir). These results augment the limited amount of direct evidence which indicates that FMR1 mutation patterns in leukocytes are a good, albeit potentially fallible, reflection of such patterns in the brain. This report further demonstrates the feasibility of using ON samples to evaluate the FMR1 mutation in humans in vivo.

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

“…Indeed, several investigators have pointed out that FMRP in the blood is synthesized in leukocytes, a tissue of mesodermal origin. In contrast, brain FMRP is of ectodermal origin (Abrams et al 1999;Tassone et al 1999a;Willemsen et al 1999). In addition, we measured the effects of FMRP at 11 and 15 years of age, when intellectual functioning was already rather severely impaired.…”

Application of olfactory tissue and its neural progenitors to schizophrenia and psychiatric research

“…In Rett syndrome, which is due to a mutation in the methyl-CpG binding protein 2 ( MECP2 ) gene, biopsies of nasal epithelium containing ORNs revealed several abnormalities compared to controls, including dysmorphic neurons, as well as an increased ratio of immature to mature neurons [51]. Finally, continuous cell lines of olfactory neuroblasts were used to study the fragile X mental retardation 1 (FMR1) mutation in patients with fragile X syndrome [52]. …”

Disease-specific, neurosphere-derived cells as models for brain disorders

“…The olfactory mucosa, the organ of smell in the nose, is a neural tissue that is accessible in human adults (Féron et al, 1998) and demonstrates disease-dependent alterations in cell biology in Alzheimer's disease, Rett syndrome, fragile X syndrome and SZ (Wolozin et al, 1992a;Abrams et al, 1999;Féron et al, 1999;Arnold et al, 2001;Ronnett et al, 2003;McCurdy et al, 2006). The olfactory sensory neurons are replaced by neurogenesis that continues throughout adult life from stem cells on the basement membrane (Mackay-Sim and Kittel, 1991;Leung et al, 2007).…”