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

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

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

One-way sensitivity analysis.

<p>Tornado graph showing results of one-way sensitivity analysis derived from probabilistic method. These figures indicating parameters which have the largest effect on incremental cost effectiveness ratio or ICER (THB per QALY gained) when they are varied individually. IPD = cost of inpatient care; OPD = cost of outpatient care.</p

Simplified-decision-tree.

<p>Comparing the strategies of expanding the newborn screening programme with the pre-expanded newborn screening programme. MS/MS = Tandem mass spectrometry; PKU = phenylketonuria; M = Markov model.</p

Cost-effectiveness plane.

<p>Monte Carlo simulation results on cost-effectiveness plane for the expanded newborn screening showing interval estimates for cost, outcome and incremental cost-effectiveness ratio. The figure shows the horizontal I-bar representing the 95% uncertainty interval on life-year gained, the vertical I-bar representing the 95% uncertainty interval on incremental cost, and the wedge represent the 95% uncertainty interval on the ICER. THB = Thai baht; ICER = incremental cost effectiveness ratio.</p

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

<p>^a 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

Markov model.

<p>Health states transition of selected IEM. (A) represents PKU, IVA, MSUD and MCD; (B) represents MMA; and (C) represents PA. PKU = phenylketonuria; IVA = isovaleric acidemia; MMA = methylmalonic acidemia; PA = propionic acidemia; MSUD = maple syrup urine disease; MCD = multiple carboxylase deficiency.</p

Health utility weight of IEM patients.

<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.

<p>^aCalculated 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