Favorable function of Ectonucleoside triphosphate diphosphohydrolase 1 high expression in thyroid carcinoma

Background Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) has been proved to play a vital role in human cancers. Nevertheless, the exact role of ENTPD1 in thyroid carcinoma (THCA) remained unclear. This study aimed to evaluate its prognostic value and reveal the potential regulatory mechanism in THCA. Results (1) Higher expression of ENTPD1 was found in THCA tissue compared with normal tissue (all P < 0.05). ENTPD1 expression was associated with age, sub-type and clinical stage of THCA patients (all P < 0.05). Immunohistochemistry showed its higher expression in patients with early stage. (2) ENTPD1 high expression was associated with favorable overall survival of THCA patients (all P < 0.05), especially for male patients and those with advanced stage, B-cells and Natural killer T-cells decreased (all P < 0.05). (3) Pathway analysis indicated that ENTPD1 mainly participated in metabolic process and negatively regulated metabolism-related pathway such as butanoate metabolism, pyruvate metabolism and fatty acid metabolism ((all P < 0.05). (4) ENTPD1 appeared genetic alteration in THCA, and the main mutation type of ENTPD1 was missense substitution (15.89%). (5) A weak correlation between ENTPD1 expression and methylation was found (P < 0.001). Methylation of ENTPD1 in THCA was lower than in normal group (P < 0.001), but it did not correlate with any clinical phenotypes of THCA patients. Conclusions ENTPD1 was highly expressed in THCA, and ENTPD1 high expression contributed to the prognosis of THCA patients. The present study inferred that ENTPD1 might serve as a metabolism-related gene and play a critical role in THCA through regulating metabolic pathways.

Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy

STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.

Urinary coenzyme Q10 as a diagnostic biomarker and predictor of remission in a patient with ADCK4-associated Glomerulopathy: a case report

Background AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy is a mitochondrial nephropathy caused by mutations in the ADCK4 gene, which disrupt coenzyme Q10 biosynthesis. Case presentation We report the case of a 25-year-old female patient with ADCK4-associated glomerulopathy presenting with proteinuria (and with no additional systemic symptoms). A known missense substitution c.737G > A (p.S246N) and a novel frameshift c.577-600del (p.193-200del) mutation were found. We followed the patient for 24 months during supplementation with coenzyme Q10 (20 mg/kg/d – 30 mg/kg/d) and describe the clinical course. In addition, we measured serum and urine coenzyme Q10 levels before and after coenzyme Q10 supplementation and compared them with those of healthy control subjects. The patient’s urinary coenzyme Q10 to creatinine ratio was higher than that of healthy controls before coenzyme Q10 supplementation, but decreased consistently with proteinuria after coenzyme Q10 supplementation. Conclusions Although the use of urinary coenzyme Q10 as a diagnostic biomarker and predictor of clinical remission in patients with ADCK4-associated glomerulopathy should be confirmed by larger studies, we recommend measuring urinary coenzyme Q10 in patients with isolated proteinuria of unknown cause, since it may provide a diagnostic clue to mitochondrial nephropathy.

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) forms a heterodimeric complex with U2AF2 that is primarily responsible for 3ʹ splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). The U2AF heterodimer also has a noncanonical function as a translational regulator. Here, we report that the U2AF1-S34F mutation results in specific misregulation of the translation initiation and ribosome biogenesis machinery. The net result is an increase in mRNA translation at the single-cell level. Among the translationally up-regulated targets of U2AF1-S34F is Nucleophosmin 1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of the U2AF1-S34F mutant cells and causes ribosomal RNA (rRNA) processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1, and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation that recapitulates translational misregulation in myeloid disease.

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

Background: The aim of this study was to identify genetic factors and chromosomal regions contributing to osteonecrosis of the femoral head (ONFH) in a Chinese family with presentations of Legg-Calvé-Perthes Disease (LCDP). Methods: In this study, we performed whole exon sequencing of a Chinese family with LCPD for mutation detection. Ten members had ONFH in twenty-seven family members in four generations family, 5 unaffected members of the studied family and 5 normal peoples as control were underwent whole exome sequencing for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. Results: In this Chinese family affected by LCPD, the mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain was present in 10 patients but absent in 5 unaffected members of the studied family and in 5 control chromosomes from unaffected individuals of matched geographical ancestry. The COL2A1 gene mutation was further validated by Sanger sequencing, confirmed that were heterozygous for the mutation. Then, we identified the p.Gly1170Ser mutation in exon 50 of COL2A1 in a Chinese family with LCPD. Conclusions: This study maps the mutation of mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain in a Chinese family of LCPD, which causes osteonecrosis of femoral head.

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

U2AF1 forms a heterodimeric complex with U2AF2 that is primarily responsible for 3’ splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome and Acute Myeloid Leukemia, and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). However, the U2AF heterodimer also has a non-canonical function as a translational regulator. Here, we report that the U2AF1 S34F mutation results in specific mis-regulation of the translation initiation and ribosome biogenesis machinery, with the potential for widespread translational changes. The net result is a global increase in mRNA translation at the single cell level. Among the translationally upregulated targets of U2AF1-S34F are Nucleophosmin1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of wt/S34F cells and causes rRNA processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1 and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation which recapitulates translational mis-regulation in myeloid disease.

A Case of Ceftriaxone-Induced Acute Generalized Exanthematous Pustulosis/Generalized Pustular Psoriasis Overlap

Acute generalized exanthematous pustulosis, characterized by subcorneal or superficial intraepidermal pustules, is induced by drugs in more than 90% of cases. Psoriasis is an autoimmune disease triggered by different conditions in genetically susceptible people. Generalized pustular psoriasis is an acute and severe clinical form of psoriasis, which usually occurs in patients with psoriasis undergoing aggravating factors. In this report the authors have reported a 40-year-old male patient with primary syphilis who developed generalized pustular dermatosis after the use of ceftriaxone. On the third day after ceftriaxone treatment, complete regression of the syphilis lesions was reached. While on the sixth day, erythematous pustular lesions accompanied with fever were observed on the whole body. A personal history of psoriasis and histopathological findings with psoriasiform changes and subcorneal pustule favored the diagnosis. After discontinuation of ceftriaxone, the patient’s condition slowly improved until he had plaque-type psoriasis 3 weeks later. A heterozygous c.115 + 6T>C missense substitution of IL36RN related to the pathogenesis of acute generalized exanthematous pustulosis/generalized pustular psoriasis was identified.

A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.