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ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal
  1. Elysa Marco (marcoe{at}neuropeds.ucsf.edu)
  1. University of California, San Francisco, United States
    1. Fatima E Abidi (fatimaabidi{at}ggc.org)
    1. Greenwood Genetic Center, United States
      1. James Bristow (jbristow{at}lbl.gov)
      1. Joint Genome Institute, Lawrence Berkeley National Laboratories, United States
        1. Willow B Dean (willow.dean{at}ucsf.edu)
        1. University of California, San Francisco, Cardiovascular Research Institute, United States
          1. Philip D Cotter (pcotter{at}itsa.ucsf.edu)
          1. Biocept Laboratories, United States
            1. Rita J Jeremy (jeremyr{at}peds.ucsf.edu)
            1. University of California, San Francisco, Pediatric Clinical Research Center, United States
              1. Charles E. Schwartz (ceschwartz{at}ggc.org)
              1. JC Self Research Institute, United States
                1. Elliott H Sherr (sherre{at}neuropeds.ucsf.edu)
                1. University of California, San Francisco, Department of Neurology, United States

                  Abstract

                  Introduction: 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. Objective: We aimed to identify whether a single gene or gene region caused her cognitive and behavioral impairment and that of others. Results: Fluorescent in situ hybridization (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). The telomeric break lies in a gene poor region. We also found that the levels of the ARHGEF9 transcript from the patient are ten-fold less than those found in control samples. Consequently, we sequenced the coding exons and intron/exon borders of the ARHGEF9 gene in 99 probands from families with X linked mental retardation (XLMR) and 477 mentally retarded males in whom a diagnosis of Fragile X syndrome had been excluded. We did not identify any pathogenic changes; however we did identify intronic nucleotide changes that might alter splicing. Conclusion: ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the developing and adult 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. While ARHGEF9 appears to be an uncommon cause of mental retardation in males, it should be considered in patients with mental retardation and sensory hyperarousal.

                  • ARHGEF9
                  • Collybistin
                  • X linked mental retardation
                  • hyperarousal
                  • hyperekplexia

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