15 research outputs found

    Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

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    Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

    Ichthyosis Follicularis with Atrichia and Photophobia Syndrome: First Case Report in Thailand

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    We herein describe the first reported case of Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome in Thailand. A 6-year-old boy presented with a history of photophobia since 1 month of age. Then he developed widespread follicular hyperkeratotic papules and subtotal non-scarring alopecia by the age of 10 months and 5 years, respectively. Sparse eyelashes and nail dystrophy were also noted. No neurological abnormalities, systemic involvement, and hearing impairment were observed. The clinical manifestations were consistent with IFAP syndrome, although genetic testing did not confirm the diagnosis of this rare disorder

    BMPER Mutation in Diaphanospondylodysostosis Identified by Ancestral Autozygosity Mapping and Targeted High-Throughput Sequencing

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    Diaphanospondylodysostosis (DSD) is a rare, recessively inherited, perinatal lethal skeletal disorder. The low frequency and perinatal lethality of DSD makes assembling a large set of families for traditional linkage-based genetic approaches challenging. By searching for evidence of unknown ancestral consanguinity, we identified two autozygous intervals, comprising 34 Mbps, unique to a single case of DSD. Empirically testing for ancestral consanguinity was effective in localizing the causative variant, thereby reducing the genomic space within which the mutation resides. High-throughput sequence analysis of exons captured from these intervals demonstrated that the affected individual was homozygous for a null mutation in BMPER, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. Mutations in BMPER were subsequently found in three additional DSD cases, confirming that defects in BMPER produce DSD. Phenotypic similarities between DSD and Bmper null mice indicate that BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development

    Health utility weight of IEM patients.

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    <p>PKU = phenylketonuria; IVA = isovaleric acidemia; MMA = methylmalonic acidemia; PA = propionic acidemia; MSUD = maple syrup urine disease; MCD = multiple carboxylase deficiency</p><p>Health utility weight of IEM patients.</p

    Means and standard error (SE) of cost parameters presented in 2013 Thai Baht.

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    <p><sup>a</sup>Calculated at patient weight 1 kilogram.</p><p>NSCO = Neonatal Screening Operation Centre; PKU = phenylketonuria; IVA = isovaleric acidemia; MMA = methylmalonic acidemia; PA = propionic acidemia; MSUD = maple syrup urine disease; MCD = multiple carboxylase deficiency</p><p>1 I$ = 17.79 THB.</p

    Acceptability curve.

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    <p>The graph shows the probabilities of each strategy being cost-effective at a given ceiling ratio. The dashed lines represent the willingness to pay thresholds for the adoption of health interventions in Thailand.</p

    Mean and standard error (SE) of transitional probabilities used in the model.

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    <p><sup>a</sup> See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134782#pone.0134782.s001" target="_blank">S1 Table</a> for death from other causes.</p><p>PKU = phenylketonuria; IVA = isovaleric acidemia; MMA = methylmalonic acidemia; PA = propionic acidemia; MSUD = maple syrup urine disease; MCD = multiple carboxylase deficiency; RR = Relative risk of early-diagnosed patients compared with clinical diagnosed patients</p><p>Mean and standard error (SE) of transitional probabilities used in the model.</p
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