RESUMO
TRPM6 is predominantly expressed in the kidney and colon and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis and plays important roles in epithelial magnesium transport and the active magnesium absorption. In this study, we present a 70-day-old Iranian female patient from consanguineous parents with hypomagnesemia and secondary hypocalcemia. She presented with seizures 19 days after birth and refractory watery non-bloody diarrhea. She consequently had failure to thrive. Other features included hypotonia, wide anterior fontanel, ventriculomegaly, and pseudotumor cerebri following administration of nalidixic acid. She had severe hypomagnesemia and hypocalcemia which were treated with magnesium and calcium supplementation. Despite initial unstable response to supplemental magnesium, she eventually improved and the diarrhea discontinued. The patient was discharged by magnesium and calcium therapy. At the last follow-up at age 2.5 years, the patient remained well without any recurrence or complication. Genetic testing by whole-exome sequencing revealed a novel homozygous frameshift insertion-deletion (indel) variant in exon 26 of the TRPM6 gene, c.3693-3699del GCAAGAG ins CTGCTGTTGACATCTGCT, p.L1231Ffs*36. Segregation analysis revealed the TRPM6 heterozygous variant in both parents. Patients with biallelic TRPM6 pathogenic variants typically exhibit hypomagnesemia with secondary hypocalcemia and present with neurologic manifestations including seizures. In some patients, this is also complicated by chronic diarrhea and failure to thrive. Long-term complications are rare and most of the patients show a good prognosis with supplemental magnesium therapy.
Assuntos
Hipocalcemia , Canais de Cátion TRPM , Feminino , Humanos , Cálcio , Diarreia/etiologia , Diarreia/complicações , Insuficiência de Crescimento/etiologia , Hipocalcemia/diagnóstico , Hipocalcemia/genética , Irã (Geográfico) , Magnésio , Convulsões/complicações , Canais de Cátion TRPM/genética , IdosoRESUMO
BACKGROUND: Different genetic variants, including the single-nucleotide polymorphisms (SNPs) present in microRNA recognition elements (MREs) within 3'UTR of genes, can affect miRNA-mediated gene regulation and susceptibility to a variety of human diseases such as multiple sclerosis (MS), a disease of the central nervous system. Since the expression of many genes associated with MS is controlled by microRNAs (miRNAs), the aim of this study was to analyze SNPs within miRNA binding sites of some neuronal genes associated with MS. MATERIALS AND METHODS: Fifty-seven neuronal genes related to MS were achieved using dbGaP, DAVID, DisGeNET, and Oviddatabases. 3'UTR of candidate genes were assessed for SNPs, and miRNAs' target prediction databases were used for predicting miRNA binding sites. RESULTS: Three hundred and eight SNPs (minor allele frequency >0.05) were identified in miRNA binding sites of 3'UTR of 44 genes. Among them, 42 SNPs in 22 genes had miRNA binding sites and miRNA prediction tools suggested 71 putative miRNAs binding sites on these genes. Moreover, in silico analysis predicted 22 MRE-modulating SNPs and 22 MRE-creating SNPs in the 3'UTR of these candidate genes. CONCLUSIONS: These candidate MRE-SNPs can alter miRNAs binding sites and mRNA gene regulation. Therefore, these genetic variants and miRNAs might be involved in MS susceptibility and pathogenesis and hence would be valuable for further functional verification investigation.
RESUMO
The hallmark of multiple sclerosis (MS) pathogenesis is the breakdown of peripheral tolerance in the immune system. However, its molecular mechanism is not completely understood. Since long non-coding RNAs (lncRNAs) has played important roles in regulation of immunological pathways, here, we evaluated the expression of a novel lncRNA, TOB1-AS1, and its putative associated coding genes in the mechanism of maintaining immune tolerance in peripheral blood of MS patients to assess their possible roles in MS pathogenesis. In this study, 39 MS patients and 32 healthy matched controls were recruited. Real-time PCR standard curve method was used to quantify transcript levels of TOB1-AS1, TOB1, SKP2, and TSG. In addition, the potential sex hormone receptor binding sites on target genes promoter were analyzed using JASPR software. This work demonstrates a negative correlation between TOB1-AS1 expression and EDSS of patients. Also, a robust dysregulation of co-expression of TOB1-AS1 lncRNA and the coding genes in MS patients compared to controls was observed. Such dysregulation in this pathway may be related to MS pathogenesis and response to interferon treatment.
Assuntos
Tolerância Imunológica/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , RNA Longo não Codificante/imunologia , Adulto , Simulação por Computador , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Interferon beta/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/química , RNA Longo não Codificante/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Quinases Associadas a Fase S/biossíntese , Proteínas Quinases Associadas a Fase S/química , Proteínas Quinases Associadas a Fase S/genética , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
AIMS: Coronary artery disease (CAD) can be classified as an inflammatory disease, which affected by type 2 diabetes mellitus (T2DM). Elevated levels of many inflammatory molecules were found in the serum of patients with CAD. STAT3 molecule as a transcription factor plays an important role in the cytokines expression. Here, we examined the expression levels of STAT3 and its important regulatory genes lnc-DC and SOCS1, in patients with CAD and T2DM. METHODS: Blood samples were obtained from 37 CAD+ and 36 CAD- patients. These patients were enrolled in this study based on angiography findings and categorized based on T2DM status. The expression levels of STAT3, lnc-DC and SOCS1 genes were examined with Real time PCR method. RESULTS: A significant increase was observed in expression of STAT3 and lnc-DC genes but not SOCS1 in CAD+ versus CAD- patients. These results replicated partially in some groups categorized based on T2DM and CAD status. However, severity of CAD had no effect on expressions of these genes. Moreover, we found some significant correlations between expressions of lnc-DC with SOCS1 and STAT3, which confirmed by in silico analysis. CONCLUSION: Our results shed further light to the inflammatory aspects of CAD and T2DM with emphasis to JAK/STAT pathway and the regulatory role of long non-coding RNAs in the physiopathology of these diseases.