The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum.

BACKGROUND: The ultra-rare autosomal recessive genetic disorder, You-Hoover-Fong Syndrome (YHFS), is caused by defects in the TELO2 gene and is characterized by intellectual disability, developmental delay, and ocular impairments. This study aims to contribute to a better understanding of YHFS by reviewing previous cases and introducing a novel variant in a new case. METHODS: Whole exome sequencing (WES) was conducted on the proband to identify genetic variants, and Sanger sequencing was used to confirm variants within the family. This article presents a comprehensive collection of reported cases of YHFS, incorporating both molecular and clinical data, through an extensive literature search and analysis of English-language studies published until June 2023. RESULTS: Using WES, a novel homozygous missense variant, c.1799A > G (p. Tyr600Cys), was identified in the TELO2 gene in a 4-year-old Iranian male patient. Novel clinical features, including choanal atresia and clubfoot, were also identified. A comprehensive literature review identified 27 patients with YHFS, with 20 variants in the TELO2 gene. Missense pathogenic variants were the most common type of pathogenic variant, and the most common features were microcephaly and intellectual impairment. CONCLUSION: This study presents the first case of pathogenic variants in TELO2 gene in Iran, expands the genotypic and phenotypic spectrum of YHFS and contributes to the growing body of literature pertaining to YHFS. Furthermore, our findings highlight the importance of genetic testing for non-consanguineous carrier screening, as compound heterozygosity may be a significant factor in the development of YHFS. Further research is needed to clarify the molecular mechanisms underlying YHFS pathogenesis.

Broadening the Phenotype and Genotype Spectrum of Glycogen Storage Disease by Unraveling Novel Variants in an Iranian Patient Cohort.

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders.

NK cell therapy in relapsed refractory multiple myeloma.

Recent advances in adoptive cell therapy have considerably changed the paradigm of cancer immunotherapy. Although current immunotherapies could cure many patients with multiple myeloma (MM), relapsed/refractory MM (RR/MM) is still challenging in some cases. Natural killer (NK) cells are innate immune cells that exert effective cytotoxic activity against malignant cells like myeloma cells. In addition to their antitumor properties, NK cells do not induce graft versus host disease following transplantation. Therefore, they provide a promising approach to treating RR/MM patients. Currently, attempts have been made to produce large-scale and good manufacturing practices (GMP) of NK cells. Ex vivo expanded/activated NK cells derived from the own patient or allogenic donors are potential options for NK cell therapy in MM. Besides, novel cell-based products such as NK cell lines and chimeric antigen receptor (CAR)-NK cells may provide an off-the-shelf source for NK cell therapy. Here, we summarized NK cell activity in the MM microenvironment and focused on different NK cell therapy methods for MM patients.

Correlated downregulation of VDR and CYP3A4 in colorectal cancer.

BACKGROUND: The evidence obtained from experimental studies suggests the tumor-suppressive effects of vitamin D by controlling the differentiation, proliferation, and apoptosis in cancerous cells. Furthermore, the deregulation of genes involved in vitamin D metabolism has been reported in several types of cancer. METHODS: In the present study, we investigated the expression level of vitamin D metabolic pathway genes, including VDR, CYP3A4, RXRα, and GC, in colorectal cancer (CRC) samples compared with the adjacent tissues by using quantitative RT-PCR. RESULTS: The results indicated significant downregulation of CYP3A4 and VDR genes in CRC tissues compared with the adjacent control tissues (p < 0.01). RXRA and GC expression levels did not show any significant alteration among the studied samples. Moreover, a positive correlation was observed between the expression level of CYP3A4 and VDR genes (p < 0.0001). ROC curve analysis also revealed the potential diagnostic power of CYP3A4 and VDR genes in CRC samples. CONCLUSION: Reduction in the expression of both CYP3A4 and VDR plays an important role in CRC due to the possible impairment in vitamin D metabolism. Further studies concerning the relationship between the expression of these genes and colorectal cancer pathogenesis and treatment are recommended.

SBF2-AS1 and TreRNA: novel lncRNA players in triple-negative breast cancer pathogenesis.

BACKGROUND: Compared to other breast cancer subtypes, triple-negative breast cancer (TNBC) has always been challenging for clinicians due to its aggressive behavior and lack of a specific treatment. There is a confirmed association between invasive features of tumors and increased epithelial-mesenchymal transition (EMT) process, which is consistent with a higher rate of EMT in TNBC. METHODS AND RESULTS: We investigated the expression of EMT-related genes, SNAI1 and MMP7, and EMT-related lncRNAs, treRNA and SBF2-AS1, in 50 TNBC tumors and 50 non-TNBC tumors to reveal more regulators and effectors involved in TNBC malignancy. In the present study, we showed the overexpression of all the studied genes and lncRNAs in TNBC tumors compared to non-TNBC samples. Moreover, a significant association was observed between MMP7 and treRNA expression levels and larger tumor size. A positive correlation between SNAI1 and lncRNA treRNA expression levels was also detected. CONCLUSIONS: Due to the differential expression and the potential diagnostic power of the studied genes, SBF2-AS1 and treRNA can be proposed as new probable biomarkers and therapeutic targets in TNBC.

Alopecia areata-like pattern of baldness: the most recent update and the expansion of novel phenotype and genotype in the CTNNB1 gene.

Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant genetic disorder caused by genetic alterations in the CTNNB1 gene. CTNNB1 is a gene that encodes ß-catenin, an effector protein in the canonical Wnt pathway involved in stem cell differentiation and proliferation, synaptogenesis, and a wide range of essential cellular mechanisms. Mutations in this gene are also found in specific malignancies as well as exudative vitreoretinopathy. To date, only a limited number of cases of this disease have been reported, and though they share some phenotypic manifestations such as intellectual disability, developmental delay, microcephaly, behavioral abnormalities, and dystonia, the variety of phenotypic traits of these patients shows extreme heterogeneity. In this study, two cases of NEDSDV with de novo CTNNB1 mutations: c.1420C>T(p.R474X) and c.1377_1378Del(p.Ala460Serfs*29), found with whole exome sequencing (WES) have been reported and the clinical and paraclinical characteristics of these patients have been described. Due to such a wide range of clinical characteristics, the identification of new patients and novel variants is of great importance in order to establish a more complete phenotypic spectrum, as well as to conclude the genotype-phenotype correlations in these cases.

Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection.

Infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) is caused by biallelic mutations in the NALCN gene, the major ion channel responsible for the background Na + conduction in neurons. Through whole-exome sequencing (WES), we report three novel homozygous variants in three families, including c.1434 + 1G > A, c.3269G > A, and c.2648G > T, which are confirmed and segregated by Sanger sequencing. Consequently, intron 12's highly conserved splice donor location is disrupted by the pathogenic c.1434 + 1G > A variation, most likely causing the protein to degrade through nonsense-mediated decay (NMD). Subsequently, a premature stop codon is thus generated at amino acid 1090 of the protein as a result of the pathogenic c.3269G > A; p.W1090* variation, resulting in NMD or truncated protein production. Lastly, the missense mutation c.2648G > T; p.G883V can play a critical role in the interplay of functional domains. This study introduces recurrent urinary tract infections for the first time, broadening the phenotypic range of IHPRF1 syndrome in addition to the genotypic spectrum. This trait may result from insufficient bladder emptying, which may be related to the NALCN channelosome's function in background Na + conduction. This work advances knowledge about the molecular genetic underpinnings of IHPRF1 and introduces a novel phenotype through the widespread use of whole exome sequencing.

Association of HOTAIR rs2366152 and rs1899663 polymorphisms with colorectal cancer susceptibility in Iranian population: A case-control study.

BACKGROUND: Despite the fact that numerous studies have investigated the association between genetic polymorphisms and colorectal cancer (CRC), more research is required to comprehend the molecular mechanisms of CRC. In the present study, we investigated the association between lncRNA HOTAIR rs2366152 and rs1899663 polymorphisms with CRC susceptibility in the Iranian population. METHODS: This case-control study consisting of 187 CRC patients and 200 healthy samples. The tetra-amplification refractory mutation system-polymerase chain reaction (Tetra-ARMS-PCR) technique was used for the genotyping of rs2366152 and rs1899663 polymorphisms. RESULTS: The findings showed that the AG genotype of the rs2366152 polymorphism has a protective effect on CRC susceptibility (OR = 0.60, 95% CI: 0.38-0.94, p-value = 0.023). Furthermore, rs2366152 polymorphism associated with CRC risk in an over dominant inheritance model (p-value = 0.0089). According to the outcomes of the rs1899663 polymorphism, the GT genotype had protective effects on CRC risk (OR = 0.55, 95% CI: 0.35-0.86, p-value = 0.008). Moreover, statistical analysis has shown that the rs1899663 polymorphism was associated with CRC risk in dominant (p-value = 0.013) and overdominant (p-value = 0.0086) inheritance models in the Iranian population. CONCLUSION: This study confirmed that HOTAIR rs2366152 and rs1899663 polymorphisms associated with CRC risk in different inheritance models. It is indeed necessary to do additional research to verify our findings.

Long non-coding RNA MIR4435-2HG: a key molecule in progression of cancer and non-cancerous disorders.

MIR4435-2HG (LINC00978) is a long non-coding RNA (lncRNA) that acts as an oncogene in almost all cancers. This lncRNA participates in the molecular cascades involved in other disorders such as coronary artery diseases, osteonecrosis, osteoarthritis, osteoporosis, and periodontitis. MIR4435-2HG exerts its functions via the spectrum of different mechanisms, including inhibition of apoptosis, sponging microRNAs (miRNAs), promoting cell proliferation, increasing cell invasion and migration, and enhancing epithelial to mesenchymal transition (EMT). MIR4435-2HG can regulate several signaling pathways, including Wnt, TGF-ß/SMAD, Nrf2/HO-1, PI3K/AKT, MAPK/ERK, and FAK/AKT/ß­catenin signaling pathways; therefore, it can lead to tumor progression. In the present review, we aimed to discuss the potential roles of lncRNA MIR4435-2HG in developing cancerous and non-cancerous conditions. Due to its pivotal role in different disorders, this lncRNA can serve as a potential biomarker in future investigations. Moreover, it may serve as a potential therapeutic target for the treatment of various diseases.

Expression of ERBB gene family in females with breast cancer and its correlation with clinicopathological characteristics of the disease.

BACKGROUND: Breast cancer (BC) is the most prevalent and fatal cancer in women. Given that there are very few studies investigating the overexpression of four members of ERBB genes, we decided to investigate the correlation between these four genes with clinicopathological characteristics in breast cancer cases. METHODS: Tumoural tissue of 50 patients with sporadic invasive ductal BC was recruited. Also, control samples were provided from adjacent non-cancerous tissues (ANCTs) of the same patients. The expression of four ERBB genes was evaluated by real-time PCR and its correlation with clinicopathological characteristics was assessed. RESULTS: Only ERBB2 (HER2) was overexpressed in tumoural tissue compared with ANCTs. Our data showed a significant relationship between ERBB1 overexpression with triple-negative tumors, ER, and PR negativity (P < 0.05). Also, ERBB2 overexpression indicated a significant correlation with several pathological characteristics such as age < 50, tumor size larger than 2 cm, early and advanced stages, negative involved lymph nodes, luminal B, triple-negative, ERBB2-enrich, estrogen receptor (ER) and progesterone receptor (PR) negative tumors, Ki-67 mutation more than 15%, and finally HER2/neu immunohistochemistry (IHC) positive and intermediate (P < 0.05). Moreover, this study demonstrated that ERBB4 overexpression had a significant correlation with tumor size smaller than 2 cm, grade I and II tumors (early-stage tumors), luminal A, ER and PR positive tumors, HER-2/neu IHC intermediate, and tumors that had a Ki-67 mutation lower than 15% (P < 0.05). Besides, our analysis showed a significant correlation between the expression of ERBB1 with ERBB2 and ERBB3 with ERBB4 (P < 0.05). CONCLUSIONS: Our findings showed a significant relationship between unfavorable clinicopathological characteristics with ERBB1 and ERBB2 overexpression, but overexpression of ERBB4 was correlated with favorable outcomes.

The role of FOXC1/FOXCUT/DANCR axis in triple negative breast cancer: a bioinformatics and experimental approach.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer and does not benefit from the existing targeted therapies. In the present study, we used bioinformatics and experimental approaches to assess the genes that are somehow involved in the epithelial-mesenchymal transition (EMT) pathway which may explain the invasive features of TNBC. METHOD AND RESULTS: We analyzed five GEO datasets consisting of 657 breast tumors by GEO2R online software to achieve common differentially expressed genes (DEGs) between TNBC and non-TNBC tumors. The expression of the selected coding and non-coding genes was validated in 100 breast tumors, including fifty TNBC and fifty non-TNBC samples, using quantitative Real-Time PCR (qRT-PCR). The bioinformatics approach resulted in a final DEG list consisting of ten upregulated and seventeen downregulated genes (logFC ≥|1| and P < 0.05). Co-expression network construction indicated the FOXC1 transcription factor as a central hub node. Considering the notable role of FOXC1 in EMT, the expression levels of FOXC1-related lncRNAs, lnc-FOXCUT and lnc-DANCR, were also evaluated in the studied tumors. The results of qRT-PCR confirmed notable upregulation of FOXC1, lnc-FOXCUT, and lnc-DANCR in TNBC tissues compared to non-TNBC samples (P < 0.0001, P = 0.0005, and P = 0.0008, respectively). Moreover, ROC curve analysis revealed the potential biomarker role of FOXC1 in TNBC samples. CONCLUSION: Present study suggested that the deregulation of FOXC1/lnc-FOXCUT/lnc-DANCR axis may contribute to the aggressive features of triple-negative breast tumors. Therefore, this axis may be considered as a new probable therapeutic target in the treatment of TNBC.

Identification of a novel de novo mutation in the CTNNB1 gene in an Iranian patient with intellectual disability.

CTNNB1 encodes for the ß-catenin protein, a component of the cadherin adhesion complex, which regulates cell-cell adhesion and gene expression in the canonical Wnt signaling pathway. Mutations in CTNNB1 have been reported to be associated with cancer and mental disorders. Recently, loss-of-function mutations in CTNNB1 have been observed in patients with intellectual disability and some other clinical manifestations including motor and language delays, microcephaly, and mild visual defects. We report an 8-year-old Iranian girl with intellectual disability, hypotonia, impaired vision such as vitreomacular adhesion, motor delay, and speech delay. A novel, de novo nonsense mutation (c.1014G > A; p.Trp338Ter) in exon 7 of the CTNNB1 (NM_001904) gene was detected and confirmed by whole-exome sequencing and Sanger sequencing, respectively. This study helps to expand the growing list of loss-of-function mutations known in the CTNNB1 gene.

Autophagy ATG16L1 rs2241880 impacts the colorectal cancer risk: A case-control study.

BACKGROUND: Despite many efforts to discover the important role of the autophagy process in the pathogenesis of colorectal cancer (CRC), the exact involved molecular mechanism still remains to be elucidated. Recently, a limited number of studies have been employed to discover the impact of autophagy genes' variants on the development and progression of CRC. Here, we evaluated the association between two single-nucleotide polymorphisms (SNPs) in the main components of the autophagy genes, ATG16L1 rs2241880, and ATG5 rs1475270, and the CRC risk in an Iranian population. METHODS: During this investigation, a total of 369 subjects, including 179 CRC patients and 190 non-cancer controls have been genotyped using Tetra-primer amplification refractory mutation system-polymerase chain reaction (TP-ARMS-PCR) method. RESULT: The results demonstrated that the T allele of the ATG16L1 rs2241880 was significantly associated with the increased risk of CRC in the studied population (OR 1.64, 95% CI: 1.21-2.22, p = 0.0015). Moreover, ATG16L1 rs2241880 TT genotype increased the susceptibility to CRC (OR 3.31, 95% CI: 1.64-6.69, p = 0.0008). Furthermore, a significant association was observed under the recessive and dominant inheritance models (p = 0.0015 and p = 0.017, respectively). No statistically significant differences were found in the ATG5 rs1475270 alleles and genotypes between the cases and controls. CONCLUSION: The results of the present study may be helpful concerning the risk stratification in CRC patients based on the genotyping approach of autophagy pathways and emphasize the need for further investigations among different populations and ethnicities to refine our conclusions.

Reduced expression of CFAP44 and CFAP44-AS1 may affect sperm motility and morphology.

Motility and morphology are two important characteristics of a fertile spermatozoon. CFAP44 gene encodes flagellar protein 44 involved in the formation and function of the flagella and cilia. Long non-coding RNAs are regulatory elements involved in several processes, including reproduction. We aimed to study the alterations in the expressions of CFAP44 and CFAP44-AS1 genes in infertile men with asthenozoospermia and terato-asthenozoospermia. In this case-control study, a total of 105 subjects, including 35 TAZ patients, 34 AZ patients and 35 normozoospermic men, were enrolled. After RNA extraction from spermatozoa samples, quantitative real-time PCR was performed to compare the expression of CFAP44 and CFAP44-AS1 between the studied groups. A meaningful reduction in CFAP44 expression and a significant reduction in the expression of CFAP44-AS1 were observed. Moreover, a positive correlation between both genes' expressions and normal sperm morphology was detected in NZ, AZ and TAZ groups. Also, there was a positive relation between CFAP44 gene expression and sperm motility in AZ and TAZ groups. The expression of CFAP44-AS1 was positively correlated with sperm motility and morphology. Present results confirm the role of CFAP44 and CFAP44-AS1 in the motility and morphology of spermatozoon, and deregulation of these genes may contribute to male infertility.

Novel long noncoding RNAs upregulation may have synergistic effects on the CYP24A1 and PFDN4 biomarker role in human colorectal cancer.

Long noncoding RNAs (lncRNAs) are emerging as the master regulators of tumor initiation, proliferation, and metastasis; however, their diagnostic value as potential biomarkers should be clarified. Vitamin D influences the expression of several genes in various pathways, including the CYP24A1 gene in the vitamin D metabolism pathway. In the present research, we surveyed the expression levels and clinical significance of novel lncRNAs related to CYP24A1 and PFDN4 genes in colorectal cancer (CRC) using real-time polymerase chain reaction. Furthermore, we assessed the expression of these genes after vitamin D treatment in HCT-116 and HT-29 colon cancer cell lines. Our results indicated that the transcription of CYP24A1, PFDN4, and nearby lncRNAs was affected by vitamin D treatment in HCT-116 and HT-29 cell lines. Moreover, CYP24A1, PFDN4, lnc-CYP24A1-3:1, and lnc-TSHZ2-19:1 were upregulated and had the potential to distinguish colorectal cancer tissues from the adjacent tissues by the large area under the receiver operating characteristic curve (0.94, 0.66, 0.70, and 0.60, respectively). lnc-TSHZ2-19:1 expression level significantly correlated with gender (p = .03). In conclusion, CYP24A1, PFDN4, lnc-CYP24A1-3:1, and lnc-TSHZ2-19:1 can be used as potential diagnostic biomarkers in the specific and sensitive assessment of CRC. Besides this, vitamin D treatment may modulate the expression of these genes in a cell-specific manner.

Long noncoding RNA LINC00978 acts as a potential diagnostic biomarker in patients with colorectal cancer.

Colorectal cancer (CRC) as a lethal malignancy has been associated with dysregulation of several genes and pathways. Long noncoding RNAs (lncRNAs) play an important role in gene expression regulation. In the current research, we aim to evaluate the expression of LINC00978 in CRC samples and adjacent tissues. Using Quantitative Real-Time PCR (qRT-PCR) method, we assessed the expression levels of LINC00978 and ß-catenin in 70 pairs of CRC and adjacent tissues. Moreover, the association between clinicopathological features and the LINC00978 expression levels was investigated. To assess the diagnostic power of LINC00978 expression in CRC, receiver operating characteristic (ROC) curve was plotted. The relationship between LINC00978 and ß-catenin expression levels was evaluated using correlation analysis. A markedly increased level of LINC00978 and ß-catenin expression levels was observed in CRC samples compared with adjacent tissues (P < 0.0001). No significant association was detected between LINC00978 expression level and the patient's clinicopathological features. The results of Pearson's correlation coefficient highlighted a positive correlation between LINC00978 and ß-catenin expression (r2 = 0.4695, P < 0.0001). According to the area under curve (AUC) value, LINC00978 expression differentiates CRC samples from the adjacent tissues (AUC = 0.81, P < 0.0001). The present results suggest that LINC00978 may play a critical role in CRC progression via Wnt pathway. The potential role of LINC00978 as a diagnostic biomarker needs to be further investigated in future studies.

CREB-binding protein (CREBBP) and preeclampsia: a new promising target gene.

Preeclampsia (PE) is a major complication of pregnancy and remains a leading cause of neonatal and maternal mortality worldwide. Several studies have revealed that the incidence of preeclampsia is high in mothers who carried a fetus with Rubinstein-Taybi Syndrome due to the mutation in CREBBP. We aimed to compare the expression level of the CERBBP gene between preeclamptic and healthy placenta in our study. The expression level of CREBBP gene was evaluated in a total of one hundred placental biopsies from PE patients and healthy pregnant women after delivery using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the differential expression of CREBBP was assessed between the maternal and fetal sides of the placenta. Expression of the CREBBP gene was higher in preeclampsia patients compared with the controls (Fold change = 2.158; P = 0.018). Moreover, the gene expression was slightly higher in the fetal side of the placenta, although it was not significantly different (Fold change = 1.713, P = 0.254). Our findings show a role for CREBBP in the pathogenesis of PE. Due to the important role of CREBBP in angiogenesis and hypoxia, the gene may serve as a promising target in future studies.

The effect of granulocyte colony-stimulating factor dose and administration interval after allogeneic hematopoietic cell transplantation on early engraftment of neutrophil and platelet.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is one of the treatments for hematologic malignancies. Numerous factors affect the HSCT outcome. The purpose of this study was to investigate the effect of post-HSCT administration of granulocyte colony-stimulating factor (post-G-CSF) on early neutrophil and platelet engraftment in allogeneic HSCT (allo-HSCT). MATERIAL & METHODS: The study was performed on 76 patients diagnosed with AML and ALL. All patients underwent allo-HSCT at Taleghani stem cell transplantation center, Tehran, Iran, from February 2016 to December 2018. Chemotherapy regimens based on patients' conditions were selected between myeloablative and reduced-intensity regimens. RESULTS: Statistical analysis revealed that the number of administered G-CSF units after HSCT was a time-dependent variable. Statistical analysis before day +11 reported that patients who received G-CSF <14 units had three times better early neutrophil engraftment than those with G-CSF ≥14 (CI 95%, AHR = 3.03, p:0.002). CD3+ cells count <318.5 × 106 /kg was associated with fast platelet engraftment (CI 95%, AHR 2.28, p:0.01). CONCLUSION: In this study, post-G-CSF stimulation was associated with early engraftment in a time- and dose-dependent manner. Administration of G-CSF beyond 14 units resulted in adverse effects on neutrophil early engraftment. It also appeared that with a reduction in CD3+ cell counts, the likelihood of GVHD decreases, and platelet engraftment occurs earlier. Further investigations in the future are required to determine the factors affecting the process of early engraftment.

Dysregulation of vitamin D synthesis pathway genes in colorectal cancer: A case-control study.

BACKGROUND: The cytochromes P450 are a superfamily of enzymes that control the synthesis of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3. These enzymes contribute to the formation of 1,25-dihydroxyvitamin D3, which starts with a 25-hydroxylation by CYP2R1 and CYP27A1 and a subsequent 1α-hydroxylation via CYP27B1. METHODS: By using quantitative real-time polymerase chain reaction (qRT-PCR), we analyzed the expression ratio of CYP2R1, CYP27A1 and CYP27B1 genes within the vitamin D metabolic pathway in a total of 75 colorectal cancer (CRC) tissues compared to the adjacent tissues. Furthermore, we evaluated the association of CYP27B1 rs4646536 and CYP2R1 rs12794714 and rs10766196 polymorphisms with CRC risk in a total of 490 subjects, including 245 CRC patients and 245 non-cancer controls. The genotyping was performed using tetra-primer amplification refractory mutation system polymerase chain reaction (TP-ARMS-PCR) method. RESULTS: The results indicated 2.3 and 2.7 upregulation of CYP2R1 and CYP27B1 genes in colorectal cancer tissues compared to the adjacent tissues, respectively. Rs12794714 AG genotype increased the risk of CRC (P = .03). Furthermore, a significant association was observed under the dominant inheritance model (P = .039). CONCLUSION: CYP2R1 and CYP27B1 genes were over-expressed in CRC samples compared to the adjacent control tissues. Furthermore, CYP2R1 rs12794714 variant was associated with the risk of CRC in the studied samples. CYP2R1 rs10766196 and CYP27B1 rs4646536 are not responsible for CYP2R1 and CYP27B1 genes expression alteration, respectively, but CYP2R1 rs12794714 polymorphism may be the reason of CYP2R1 upregulation and increased the risk of CRC.

A novel SRD5A2 mutation in an Iranian family with sex development disorder.

Disorders of sex development (DSD) are different types of conditions that their accurate diagnosis by using conventional phenotypic and biochemical approaches is a challenging issue. Precise determination of DSD is critical due to the detection of possible life-threatening associated disorders. It may also assist parents in choosing the most suitable management for their affected child. In this study, two affected kids born from consanguineous families who were clinically diagnosed for sex development disorder were investigated for the main cause of the disease. Biochemical analysis failed to make an accurate diagnosis. Karyotype analysis showed an abnormal sex chromosome pattern. Whole exome sequencing was sequentially applied to precisely ascertain the genetic cause of the disease. A novel deletion, g.40936_53878del12943insTG (NG_008365.1), and one known mutation, c.586G>A (p.Gly196Ser), were detected in SRD5A2 gene in case I and case II respectively. Further analysis was performed using polymerase chain reaction, primer walking and Sanger sequencing to detect the nucleotides changes accurately. Segregation analysis in the families confirmed 13kb novel homozygous deletion of SRD5A2 in case I and c.586G>A in case II. The present study confirms the diagnostic value of whole exome sequencing in the detection of DSD aetiology, especially when several differential diagnoses are possible.