Small genomic rearrangements involving FMR1 support the importance of its gene dosage for normal neurocognitive function

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX, 77030, USA, .
Neurogenetics (Impact Factor: 2.88). 08/2012; 13(4):333-9. DOI: 10.1007/s10048-012-0340-y
Source: PubMed


Fragile X syndrome, the most common form of X-linked intellectual disability, results from transcriptional silencing of the FMR1 gene. As of yet, the phenotypic consequences of the duplication of FMR1 have not been well characterized. In this report, we characterize the clinical features in two females with duplications involving only the FMR1 gene. In addition, we describe the phenotypes of two subjects with deletion of FMR1 and show that both loss and gain of FMR1 copy number can lead to overlapping neurodevelopmental phenotypes. Our report supports the notion that FMR1 gene dosage is important for normal neurocognitive function.

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Available from: Sau Wai Cheung, Dec 10, 2014
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    • "A clinical report of two cases with duplications of the FMR1 gene and two cases with deletion of FMR1 showed that “both loss and gain of FMR1 copy number can lead to overlapping neurodevelopmental phenotypes” (Nagamani et al., 2012, p. 333). Ramocki and Zoghbi (2008) articulated the necessity of tight neuronal homeostatic control mechanisms for normal cognition and behavior, and suggested that neurodevelopmental and neuropsychiatric disorders may in part be the result of imbalances in homeostatic controls in multiple genes, including FMR1. "
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    ABSTRACT: Fragile X Syndrome (FXS) is the leading known monogenic form of autism and the most common form of inherited intellectual disability. FXS results from silencing the FMR1 gene during embryonic development, leading to loss of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein that regulates mRNA transport, stability, and translation. FXS is commonly thought of as a disease of synaptic dysfunction, however, FMRP expression is lost early in embryonic development, well before most synaptogenesis occurs. Recent studies suggest that loss of FMRP results in aberrant neurogenesis, but neurogenic defects have been variable. We investigated whether FMRP affects neurogenesis in Xenopus laevis tadpoles which express a homolog of FMR1. We used in vivo time-lapse imaging of neural progenitor cells and their neuronal progeny to evaluate the effect of acute loss or over-expression of FMRP on neurogenesis in the developing optic tectum. We complimented the time-lapse studies with SYTOX labeling to quantify apoptosis and CldU labeling to measure cell proliferation. Animals with increased or decreased levels of FMRP have significantly decreased neuronal proliferation and survival. They also have increased neuronal differentiation, but deficient dendritic arbor elaboration. The presence and severity of these defects was highly sensitive to FMRP levels. These data demonstrate that FMRP plays an important role in neurogenesis and suggest that endogenous FMRP levels are carefully regulated. These studies show promise in using Xenopus as an experimental system to study fundamental deficits in brain development with loss of FMRP and give new insight into the pathophysiology of FXS.
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