Mutations in the _SC4MOL_ gene encoding a novel methyl sterol oxidase cause autosomal recessive psoriasisiform dermatitis, microcephaly and developmental delay

Disorders of cholesterol biosynthesis have clinical manifestations involving skeleton, eyes, neurologic development, and skin. We describe a patient with congenital cataracts, developmental delay, microcephaly, and low serum cholesterol who developed severe psoriasiform dermatitis and arthralgias beginning at age 3. Her brain MRI indicatedminor gliosis. Quantitative sterol analysis of patient plasma and skin showed marked elevation of 4alpha-methyl- and 4, 4'-dimethylsterols, indicating a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis. Molecular studies showed mutations in _SC4MOL_, a gene predicted to encode a sterol C4 methyl oxidase. Thus, our patient has a previously undescribed inborn error of cholesterol biosynthesis. Cellular studies with patient-derived fibroblasts showed higher mitotic rate than control cells in cholesterol-depleted medium, in which _de novo_ cholesterol biosynthesis was increased with the accumulation of methylsterol. Immunologic analyses showed dysregulation of immune-related receptors in the patient and her father. Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts or in fresh leukocytes induced activation of cell cycle, and immune receptor dysregulation. These findings suggest that methylsterols influence mitotic capacity and immune function. _SC4MOL_ is situated within the psoriasis susceptibility locus _PSORS9_, and is likely a genetic risk factor for common psoriasis

Results from a 78-week, single-arm, open-label Phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD).

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment-related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food

Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples

Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH “tag” SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case–control analyses (z = 2.99, P = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, P = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, P = 0.165), and combined analyses of all four samples were significant (rs1522305: χ2 = 23.28, 8 d.f., P  = 0.003). Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case–control results in African-Americans detected an association with L321L (P = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted

EGFR signaling and Arf6 act in the same pathway in the regulation of intrahepatic biliary morphogenesis.

<p>Instead of 4 μM AG1478 and 2 ng of <i>arf6</i>-ATG MO, 1 μM AG1478 and 0.5 ng of <i>arf6</i>-ATG MO were used. (A) Epifluorescence images showing the expression of <i>Tp1</i>:GFP and <i>fabp10a</i>:dsRed revealed a severe defect in the intrahepatic biliary structure only when the MO injection was combined with the AG1478 treatment. Based on the severity of the biliary defect, larvae were divided into three groups: normal, intermediate, and severe. Arrows point to the liver and dotted lines outline the liver. Scale bars, 100 μm. (B) Graph showing the percentage of larvae in each group shown in A. (C) Graph showing the percentage of larvae exhibiting different levels of PED-6 accumulation in the gallbladder at 5 dpf. n indicates the number of larvae examined.</p

EGFR signaling regulates biliary morphogenesis.

<p>(A) Whole-mount in situ hybridization image showing <i>egfra</i> expression in the liver at 72 hpf. (B) Confocal images of the liver showing the intrahepatic biliary structure, as revealed by <i>Tp1</i>:GFP expression. <i>Tg(Tp1</i>:<i>GFP)</i> embryos were treated with DMSO or 4 μM AG1478 from 48 to 96 hpf, and processed for whole-mount immunostaining with anti-GFP antibody. The length of BEC filopodia was quantified as shown in a graph. Brackets delineate the length of BEC filopodia. (C) Confocal images of the liver showing the expression of <i>Tp1</i>:GFP (green) and Abcb11 (red) for biliary structure and bile canaliculi, respectively. (D) Confocal images of the liver showing the location of BEC nuclei in the entire liver, as assessed by <i>Tp1</i>:H2B-mCherry expression. Dashed lines outline clusters with four or more BECs. Graph showing the percentage of BECs present as single cells, doublets, triplets, or in clusters of four or more cells. (E) Epifluorescence images showing PED-6 accumulation in the gallbladder in DMSO- or AG1478-treated larvae at 5 dpf. Graph showing the percentage of larvae exhibiting different levels of PED-6 accumulation in the gallbladder. Arrows point to the gallbladder. All dotted lines outline the liver. n indicates the number of larvae examined; asterisks indicate statistical significance (* p<0.0001). Error bars, ± SEM; scale bars, 25 μm.</p

Eigenstrat Principal Components Analysis.

<p>(A) Boxed region shows well stratified cases and controls carried forward in analysis. (B) The BA susceptibility locus defined by rs3126184 and rs10140366 lies in an enhancer region in the 3’ flanking region of the <i>ARF6</i> gene (UCSC genome browser evaluation show enriched histone marks H3K4me1 overlayed with H3K27Ac is an indicative of enhancer region). (C) i-iv show <i>ARF6</i> immunostaining in liver explants from normal children with intact bile ducts (BD) (i), children with BA with bile duct paucity in portal tracts (PT) (ii) or cirrhosis (iii), and a child with hepatocellular carcinoma (iv). T = tumor cells, L = lobule.</p