Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures

Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 11/2009; 18(4):436-41. DOI: 10.1038/ejhg.2009.199
Source: PubMed


Microdeletion of chromosome 2q23.1 results in a novel syndrome previously reported in five individuals. Many of the del(2)(q23.1) cases were thought to have other syndromes such as Angelman, Prader-Willi, or Smith-Magenis because of certain overlapping clinical features. We report two new cases of the 2q23.1 microdeletion syndrome, describe the syndrome phenotype, define the minimal critical region, and analyze the expression of critical region genes toward identification of the causative gene(s) for the disorder. Individuals with del(2)(q23.1) have severe developmental and cognitive delays, minimal speech, seizures, microcephaly, mild craniofacial dysmorphism, behavioral disorders, and short stature. The deletions encompassing 2q23.1 range from >4 Mb to <200 kb, as identified by oligonucleotide and BAC whole-genome array comparative hybridization. The minimal critical region includes a single gene, MBD5, deleted in all cases, whereas all but one case also include deletion of EPC2. Quantitative real-time PCR of patient lymphoblasts/lymphocytes showed an approximately 50% reduced expression of MBD5 and EPC2 compared with controls. With similar phenotypes among the 2q23.1 deletion patients, the idea of one or more common genes causing the pathological defect seen in these patients becomes evident. As all five previous cases and the two cases in this report share one common gene, MBD5, we strongly suspect that haploinsufficiency of MBD5 causes most of the features observed in this syndrome.

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    • "MBD proteins modulate gene expression by recruiting various partners involving in chromatin remodelling (Bogdanovic & Veenstra, 2009). Although the precise function of MBD5 is poorly understood , it was recently implicated in a human disease syndrome that includes autism spectrum disorder, microcephaly, intellectual disability, severe speech impairment, and seizures (Williams et al, 2010; Chung et al, 2011; Talkowski et al, 2011; Cukier et al, 2012; Ladha, 2012; Noh & Graham, 2012; Bonnet et al, 2013; Shichiji et al, 2013; Hodge et al, 2014; Mullegama et al, 2014). Deletion of Mbd5 in mice causes similar developmental retardation and disturbed glucose homeostasis (Du et al, 2012). "
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    ABSTRACT: Ferritin plays important roles in iron metabolism and controls iron absorption in the intestine. The ferritin subunits ferritin heavy chain (Fth1) and ferritin light chain (Ftl1) are tightly regulated at both the transcriptional and post-transcriptional levels. However, mechanisms of maintaining stable, basal expression of Fth1 are poorly understood. Here, we show that global deletion of Mbd5 in mice induces an iron overload phenotype. Liver and serum iron levels in Mbd5−/− mice were 3·2-fold and 1·5-fold higher respectively, than wild-type littermates; moreover, serum ferritin was increased >5-fold in the Mbd5−/− mice. Mbd5 encodes a member of the methyl-CpG binding domain family; however, the precise function of this gene is poorly understood. Here, we found that intestinal Fth1 mRNA levels were decreased in Mbd5−/− mice. Loss of Fth1 expression in the intestine could lead to iron over-absorption. Furthermore, deleting Mbd5 specifically in the intestine resulted in a phenotype similar to that of conditional deletion of Fth1 mice. An Fth1 promoter-report luciferase assay indicated that overexpression of Mbd5 enhanced Fth1 transcription in a dose-dependent manner. Histone H4 acetylation of the Fth1 promoter was reduced in the intestine of Mbd5−/− mice and further analysis showed that histone acetyltransferase KAT2A was essential for MBD5-induced Fth1 transcription.
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    • "Several lines of evidence have suggested that MBD5 is a single causal locus of human mental disorders. First, microdeletions of the MBD5 gene were detected in 65 patients with mental retardation [13], [14], [15], [16], [17], [18]. Second, four low-frequency missense variants in the coding sequence of MBD5 were found in mentally retarded patients but not in healthy controls [14]. "
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    ABSTRACT: Methyl-CpG binding domain protein 5 (MBD5) belongs to the MBD family proteins, which play central roles in transcriptional regulation and development. The significance of MBD5 function is highlighted by recent studies implicating it as a candidate gene involved in human 2q23.1 microdeletion syndrome. To investigate the physiological role of Mbd5, we generated knockout mice. The Mbd5-deficient mice showed growth retardation, wasting and pre-weaning lethality. The observed growth retardation was associated with the impairment of GH/IGF-1 axis in Mbd5-null pups. Conditional knockout of Mbd5 in the brain resulted in the similar phenotypes as whole body deletion, indicating that Mbd5 functions in the nervous system to regulate postnatal growth. Moreover, the mutant mice also displayed enhanced glucose tolerance and elevated insulin sensitivity as a result of increased insulin signaling, ultimately resulting in disturbed glucose homeostasis and hypoglycemia. These results indicate Mbd5 as an essential factor for mouse postnatal growth and maintenance of glucose homeostasis.
    Full-text · Article · Oct 2012 · PLoS ONE
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    • "MBD5 is expressed in the human brain, and several lines of evidence link MBD5 mutations with mental disorders. First, a microdeletion of the MBD5 gene has recently been shown to correlate with mental retardation in 8 human patients [17], [18], [19]. Additionally, 4 low-frequency missense variants in the coding sequence were found in one or more mentally retarded patients but not in healthy controls [18]. "
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    ABSTRACT: MBD5 and MBD6 are two uncharacterized mammalian proteins that contain a putative Methyl-Binding Domain (MBD). In the proteins MBD1, MBD2, MBD4, and MeCP2, this domain allows the specific recognition of DNA containing methylated cytosine; as a consequence, the proteins serve as interpreters of DNA methylation, an essential epigenetic mark. It is unknown whether MBD5 or MBD6 also bind methylated DNA; this question has interest for basic research, but also practical consequences for human health, as MBD5 deletions are the likely cause of certain cases of mental retardation. Here we report the first functional characterization of MBD5 and MBD6. We have observed that the proteins colocalize with heterochromatin in cultured cells, and that this localization requires the integrity of their MBD. However, heterochromatic localization is maintained in cells with severely decreased levels of DNA methylation. In vitro, neither MBD5 nor MBD6 binds any of the methylated sequences DNA that were tested. Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization.
    Full-text · Article · Aug 2010 · PLoS ONE
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