Evidence that SIZN1 is a Candidate X-Linked Mental Retardation Gene

Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 10/2008; 146A(20):2644-50. DOI: 10.1002/ajmg.a.32472
Source: PubMed


An estimated 1-3% of individuals within the United States are diagnosed with mental retardation (MR), yet the cause is unknown in nearly 50% of the patients. While several environmental, genetic and combined teratogenetic etiologies have been identified, many causative genes remain to be identified. Furthermore, the pathogenetic mechanisms underlying MR are known for very few of these genes. Males have a much higher incidence of MR implicating genes on the X-chromosome. We have recently identified a novel gene, SIZN1, on the X-chromosome and showed that it functions in modulating the BMP signaling pathway. Furthermore, we have shown this gene is necessary for basal forebrain cholinergic neuron (BFCN) specific gene expression. Given that cognitive function is impaired when BFCNs are lost or functionally disrupted, we undertook a screen of cognitively impaired males for SIZN1 mutations. We report on four different sequence variants in SIZN1 in 11 individuals with nonsyndromic X-linked mental retardation (XLMR). Our data implicate SIZN1 as a candidate gene for XLMR and/or as a neurocognitive functional modifier.

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Available from: Ginam Cho
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    • "Cho et al. (2008a), 2011 reported PNMA10 to be a candidate gene for X-linked mental retardation (XLMR) in humans. In mice, Pnma10/Zcchc12 is expressed in the embryonic ventral forebrain in a cholinergic–neuron-specific manner (Cho et al., 2011), and is known to act as a transcriptional co-activator for bone morphogenic protein (BMP) signaling by binding to the SMAD family of proteins (Cho et al., 2008b). "
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    • "Over the past decade mutations in numerous genes have been associated with mental retardation, yet the pathogenesis remains poorly understood in all but a few disorders. SIZN1(ZCCHC12) is one example of such a gene that, when mutated, results in mental retardation in males (Cho et al., 2008a). Biochemical studies indicate that Sizn1 is a positive modulator of BMP signaling and is necessary for normal basal forebrain cholinergic neuron gene expression (Cho et al., 2008b). "
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    ABSTRACT: Sizn1 (Zcchc12) is a transcriptional co-activator that positively modulates bone morphogenic protein (BMP) signaling through its interaction with Smad family members and CBP. We have demonstrated a role for Sizn1 in basal forebrain cholinergic neuron specific gene expression. Furthermore, mutations in SIZN1 have been associated with X-linked mental retardation. Given the defined role of SIZN1 in mental retardation, knowing its complete forebrain expression pattern is essential to further elucidating its role in cognition. To better define the dynamic expression pattern of Sizn1 during forebrain development, we investigated its expression in mouse brain development from embryonic day 8.0 (E8.0) to adult. We found that Sizn1 is primarily restricted to the ventral forebrain including the medial ganglionic eminence, the septum, amygdala, and striatum. In addition, Sizn1 expression is detected in the cortical hem and pallial-subpallial boundary (PSB; anti-hem); both sources of Cajal-Retzius cells. Sizn1 expression in the dorsal forebrain is restricted to a subset of cells in the marginal zone that also express Reln, indicative of Cajal-Retzius cells. These data provide novel information on brain regions and cell types that express Sizn1, facilitating further investigations into the function of Sizn1 in both development and the pathogenesis of mental retardation.
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