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.

Download full-text


Available from: Sau Wai Cheung, Dec 10, 2014
1 Follower
17 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This population-based study investigates genotype-phenotype correlations of "low- normal" CGG repeats in the fragile X mental retardation 1 (FMR1) gene. FMR1 plays an important role in brain development and function, and encodes FMRP (fragile X mental retardation protein), an RNA-binding protein that regulates protein synthesis impacting activity-dependent synaptic development and plasticity. Most past research has focused on CGG premutation expansions (41-200 CGG repeats) and on fragile X syndrome (200+ CGG repeats), with considerably less attention on the other end of the spectrum of CGG repeats. Using existing data, older adults with 23 or fewer CGG repeats (2 SDs below the mean) were compared with age-peers who have normal numbers of CGGs (24-40) with respect to cognition, mental health, cancer, and having children with disabilities. Men (n = 341 with an allele in the low-normal range) and women (n = 46 with two low-normal alleles) had significantly more difficulty with their memory and ability to solve day to day problems. Women with both FMR1 alleles in the low-normal category had significantly elevated odds of feeling that they need to drink more to get the same effect as in the past. These women also had two and one-half times the odds of having had breast cancer and four times the odds of uterine cancer. Men and women with low-normal CGGs had higher odds of having a child with a disability, either a developmental disability or a mental health condition. These findings are in line with the hypothesis that there is a need for tight neuronal homeostatic control mechanisms for optimal cognitive and behavioral functioning, and more generally that low numbers as well as high numbers of CGG repeats may be problematic for health.
    Frontiers in Genetics 09/2014; 5:309. DOI:10.3389/fgene.2014.00309
  • [Show abstract] [Hide abstract]
    ABSTRACT: In 1979 a "new" syndrome characterized by X-linked inheritance, hypogonadism, gynecomastia, intellectual disability, obesity, and short stature was described. The now-36-year-old propositus was recently referred to the genetics clinic for profound intellectual disability. Fragile X testing initially demonstrated a duplication of the FMR1 region, and upon further testing we identified an Xq27.3-q28 8.05 Mb-long duplication responsible for a syndrome. Our report describes the molecular and clinical aspects of the X-linked syndrome. Our results suggest that male patients with intellectual disability, hypogonadism, short stature, and gynecomastia should be further investigated for rearrangements in the Xq27.3-q28 region. In the future, when more cases of the duplication are identified, it may become possible to more accurately determine the specific genes affected by overexpression and responsible for the phenotype. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2013; 161(9). DOI:10.1002/ajmg.a.36034 · 2.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    01/2014; 2(1). DOI:10.1523/ENEURO.0055-14.2014
Show more