16 research outputs found

    Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

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    Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

    Spondylocostal dysostosis in a pregnancy complicated by confined placental mosaicism for tetrasomy 9p

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    The spondylocostal dysostoses (SCD) are a clinically and genetically heterogeneous group of disorders characterized by defects of vertebral segmentation and rib abnormalities. We report on the diagnosis of two siblings with SCD. Diagnosis was first made in a female infant following a pregnancy that was complicated by early fetal hydrops and a nuchal translucency of 8.2 mm in the first trimester. The clinical picture was complicated by the co-existent diagnosis of confined placental mosaicism (CPM) for tetrasomy 9p. To our knowledge, this is the first report of CPM for tetrasomy 9p. Postnatally the diagnosis of SCD was made on the basis of radiographic findings comprising multiple anomalies of the cervical and thoracic vertebrae and multiple fused and dysplastic ribs. Radiographic investigation of other family members showed that the infant's 4-year-old sibling had fusion of four ribs on the right side, indicating a less severe form of SCD. Testing of the genes DLL3, MESP2, and LFNG did not identify a mutation, suggesting that the siblings may have a new molecular subtype of SCD

    Characterization of speech and language phenotype in children with NRXN1 deletions

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    Neurexin 1 gene (NRXN1) deletions are associated with several neurodevelopmental disorders. Communication difficulties have been reported, yet no study has examined specific speech and language features of individuals with NRXN1 deletions. Here, we characterized speech and language phenotypes in 21 children (14 families), aged 1.8–17 years, with NRXN1 deletions. Deletions ranged from 74 to 702 kb and consisted mostly of either exons 1–3 or 1–5. Speech sound disorders were frequent (69%), although few were severe. The majority (57%) of children had difficulty with receptive and/or expressive language, although no homogeneous profiles of deficit were seen across semantic, morphological, or grammatical systems. Social language difficulties were seen in over half the sample (53%). All but two individuals with language difficulties also had intellectual disability/developmental delay. Overall, while speech and language difficulties were common, there was substantial heterogeneity in the severity and type of difficulties observed and no striking communication phenotype was seen. Rather, the speech and language deficits are likely part of broader concomitant neurodevelopmental profiles (e.g., intellectual disability, social skill deficits). Nevertheless, given the high rate of affectedness, it is important speech/language development is assessed so interventions can be applied during childhood in a targeted and timely manner

    RMI2 is necessary for localization of TopoIIIα to anaphase UFBs.

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    <p>Representative images of RMI2 wild-type and null HCT-116 cells (A) stained with anti-TopoIIIα (green), anti-PICH (red) and DAPI for DNA (blue). Scale bar 5 μm. (B) Quantification of anaphase B HCT-116 wild-type and RMI2 null cells detected with PICH and TopoIIIα. Numbers represent only the pool of anaphase B cells with PICH fibers and whether these demonstrated colocalization with TopoIIIα. The data was taken from three independent experiments, with a minimum of nine anaphase cells per experiment per cell line.</p

    Bloom-like features in two siblings with an RMI2 gene deletion.

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    <p>(A) Sibling S1 shows typical café-au-lait macules on torso that are a common feature of Bloom syndrome. (B) UCSC Genome Browser view of the homozygous deleted region that spans the entire RMI2 gene. (C) Immunoblot confirms complete loss of the RMI2 protein in each sib, S1 and S2. Heterozygous parents, P1 and P2, show the presence of RMI2. Anti-α-tubulin was used a protein loading control.</p

    RMI2 cellular defects in knockout cell lines.

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    <p>(A) Immunoblot of HCT-116 wild type and three independent RMI2 null clones (1–2, 1–3 and 4–6) confirms loss of RMI2 protein in gene knockout cells. Equivalent cell extract (40 μg) was loaded in each lane with anti-α-tubulin used as a loading control. (B) Cell proliferation analysis over three days performed in triplicate for each cell line. (C) Sister chromatid exchange analysis on parental and the three RMI2 null clones. Fifteen metaphase cells were analysed for each cell line. (D) Quantification of anaphase bridges and lagging chromosome from parental heterozygote, P1, P2, and homozygous siblings S1 and S2, and in RMI2 wild type and null HCT-116 cells. For fibroblasts (P1, P2, S1, S2) at least 200 anaphase/telophase cells were scored in total for each line from four independent experiments using matched cell passage number. For HCT-116 cells, at least 200 anaphase/telophase cells were scored for each of wild-type HCT-116, and RMI2 null clones 1–2, 1–3 and 4–6 from three independent experiments using matched cell passage number. Error bars represent standard error of the mean. (E) Colony forming and UV sensitivity assays on HCT-116 and null cell lines. The total number of colonies from three independent experiments are normalised against untreated cells. (F) Colony forming and hydroxyurea sensitivity assays on HCT-116 and null cell lines. Experiments were normalised as in the UV-challenge experiment. Error bars represent standard error of the mean.</p

    Loss of RMI2 causes significant elevation in UFBs.

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    <p>Representative images and RMI2 wild-type and null HCT-116 cells stained with anti-PICH (red) and DAPI for DNA (blue) for anaphase A (A) and anaphase B (B). Scale bar 5 μm. Quantification of PICH fiber detection in anaphase A cells in (C) and anaphase B (D) from wild-type HCT-116 control and RIM2 null cells (1–2, 1–3, 4–6). Data taken from three independent experiments, with 20 anaphase A and 20 anaphase B cells scored for each HCT-116 cell line (wild-type, 1–2, 1–3, 4–6) per experiment. Error bars represent standard error of the mean.</p

    BLM fibers are weaker in anaphase B cells lacking RMI2.

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    <p>Representative anaphase B images of parental heterozygous, P1 and P2, and homozygous siblings S1 and S2, fibroblasts (A) and RMI2 wild-type and null HCT-116 cells (D) stained with anti-BLM (green), anti-α-tubulin (red) and DAPI for DNA (blue). Scale bar 5 μm. For anaphase A analysis see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006483#pgen.1006483.s008" target="_blank">S8 Fig</a>. Quantification of BLM-staining fibers in anaphase B cells in (B) parent (P1, P2) and sibling (S1, S2), and (E) wild-type HCT-116 control and RIM2 null cells (1–2, 1–3, 4–6). Data taken from three independent experiments, with a minimum of 15 anaphase B cells scored for each fibroblast cell line (P1, P2, S1, S2) per experiment and also for each HCT-116 cell line (wild type, 1–2, 1–3, 4–6) per experiment. Error bars represent standard error of the mean. Quantification of BLM fiber intensity on fibroblast cell line (P1, P2, S1, S2) (C) and wild-type HCT-116 and RIM2 null anaphase cells (F). Data for C, F pooled from anaphase A and B cells from two independent experiments.</p

    RMI2 suppresses chromosome mis-segregation events.

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    <p>Fibroblasts grown on coverslips were fixed and then stained with DAPI. (A) Scoring of fibroblast cells with micronuclei. At least 3000 cells were scored from each of P1, P2, S1, S2 cells in matched cell passage number from four independent experiments. Example of a cell with a micronucleus is shown in inset, scale bar 15 μm. (B) Representative cells showing DNA bridges connecting interphase cells. Top panel shows normal and the bottom two panels show affected interphase cells with interconnecting DNA threads. Note the bottom cell has had the DAPI/DNA (blue) signal enhanced to visualise the DNA thread. Cells were co-stained with anti-α-tubulin (red). Scale bar 5 μm. (C) Scoring of fibroblast cells with interphase interconnecting DNA threads. At least 3000 cells were scored from each of parental control (P1, P2) and RMI2 deficient siblings (S1, S2) in matched cell passage number from three independent experiments. Error bars represent standard error of the mean.</p
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