Identification of a novel SUOX pathogenic variants as the cause of isolated sulfite oxidase deficiency in a Chinese pedigree.

BACKGROUND: Isolated sulfite oxidase deficiency (ISOD) is a life-threatening rare autosomal recessive disorder caused by pathogenic variants in SUOX (OMIM 606887) gene. The aim of our study was to establish a comprehensive genetic diagnosis strategy for the pathogenicity analysis of the SUOX gene within a limited time and to lay the foundation for precise genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis. METHODS: Two offspring from one set of parents were studied. Next-generation sequencing (NGS) was used to screen for disease-causing gene variants in a family with ISOD. Then, Sanger sequencing was performed to verify the presence of candidate variants. Sulfite, homocysteine and uric acid levels were detected in the patients. According to the ACMG/AMP guidelines, the pathogenicity level of novel variants was annotated. RESULTS: The nonsense pathogenic variant (c.1200C > G (p.Y400*)) and a duplication (c.1549_1574dup (p.I525 Mfs*102)) were found in the SUOX gene in the proband. The nonsense mutation (c.1200C > G (p.Y400*), pathogenic, isolated sulfite oxidase deficiency, autosomal recessive) has been reported as pathogenic and the duplication (c.1549_1574dup (p.I525 Mfs*102), pathogenic, isolated sulfite oxidase deficiency, autosomal recessive) was novel, which was classified as pathogenic according to the ACMG/AMP Standards and Guidelines. CONCLUSION: We established the pathogenicity assessment in ISOD patients based on ACMG/AMP Standards and Guidelines and this is the first ISOD patient reported in mainland China. We also discovered that ISOD is caused by SUOX gene duplication mutation, which enriches the spectrum of SUOX pathogenic variants.

Effects of Nicotinamide on Cervical Cancer-Derived Fibroblasts: Evidence for Therapeutic Potential.

PURPOSE: The present study aimed to examine the effects of nicotinamide (NAM) on cervical cancer-associated fibroblasts (CAF) for its in vitro efficacy, gross inhibition, and mechanism of inhibition. METHODS: The fibroblasts were treated with pre-specified concentrations of NAM followed by measurement of the cell proliferation using CCK-8 assay. The production of reactive oxygen species (ROS) was measured by 2',7'-Dichlorofluorescin diacetate. We further investigated the apoptosis by flow cytometry using Annexin-V. We employed JC-1 assay to detect changes in the potential of the mitochondrial membrane. We further determined the expression of apoptotic genes was measured using qRT-PCR. And lastly, cell cycle experiments were conducted to determine the influence of NAM on arresting the growth of CAF in a cell cycle. RESULTS: Our study showed that NAM was able to reduce fibroblasts viability. We specifically observed a significantly increased intracellular ROS with resultant exhaustion of cellular antioxidant defense machinery, including reduced glutathione (GSH). We further observed the involvement of mitochondrial pathway in the NAM induced apoptosis of fibroblasts. CONCLUSION: Our study supports the therapeutic potential of NAM for the treatment of cervical cancer and necessitates a further investigation of the reported findings.

Novel recessive PDZD7 biallelic mutations associated with hereditary hearing loss in a Chinese pedigree.

BACKGROUND: Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic disease. PDZD7 is a new ARNSHL associated gene. Until now, nine PDZD7 biallelic mutation families with ARNSHL have been reported. Here we report a case of Chinese patient with ARNSHL linked to novel mutations in PDZD7 genes. METHOD: The pathogenic mutations were detected by whole exome sequencing for hereditary deafness-related genes of both the proband and his parents. We used kinship detection, mutational hazard prediction, genotype-phenotype correlation analysis and variation screening for potential pathogenic mutations. Re-sequencing was used to confirm the mutations by Sanger sequence. Real time quantitative PCR (RT-qPCR) was used to analyze the PDZD7 gene expression. Population-based screening for variation frequency, evolutionary conservation comparisons, pathogenicity evaluation, and protein structure prediction were conducted to assess the pathogenicity of the novel mutations of PDZD7 gene. RESULTS: We determined three variants of the PDZD7 gene that contributed to the deafness of the patient (PDZD7 c.192G > A, p. Met64Ile; c.1648C > T p. Gln550* and c.2341_2352delCGCAGCCGCAGCp. Arg781_Ser 784del). Pathogenic analysis in accordance with the ACMG/AMP Standards and Guidelines identified two novel mutations as Likely Pathogenic. The expression level of PDZD7 gene in the patient was decreased compared to the normal control (P < 0.001). CONCLUSION: Three mutations in PDZD7 gene linked to ARNSHL were identified in a Chinese pedigree. The findings expand not only our knowledge of genetic causes of ARNSHL, but also PDZD7 genes mutation spectrum of the disease. They will aid personalized genetic counseling, molecular diagnostics and clinical management of this condition.