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Findings that shed new light on the possible pathogenesis of a disease or an adverse effect
ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal
  1. E J Marco1,
  2. F E Abidi2,
  3. J Bristow3,
  4. W B Dean4,
  5. P Cotter5,
  6. R J Jeremy6,
  7. C E Schwartz2,
  8. E H Sherr1
  1. 1
    Department of Neurology, University of California, San Francisco, California, USA
  2. 2
    Greenwood Genetic Center, Greenwood, South Carolina, USA
  3. 3
    Joint Genome Institute, Lawrence Berkeley National Laboratories, Berkeley, California, USA
  4. 4
    Cardiovascular Research Institute, University of California, San Francisco, California, USA
  5. 5
    Department of Pathology, Children’s Hospital and Research Center at Oakland, Oakland, California, USA
  6. 6
    Pediatric Clinical Research Center, University of California, San Francisco, California, USA
  1. Elliott H Sherr, sherre{at}neuropeds.ucsf.edu

Summary

We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome. We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others. Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient.

https://doi.org/10.1136/bcr.06.2009.1999

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    Footnotes

    • Competing interests: none.