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Polycystic ovarian syndrome (PCOS) is the most prevalent endocrine and metabolic disorder among women of reproductive age, characterized by complex polygenic influences. This study aimed to assess the role of genetic polymorphisms in the CYP2C8 gene, focusing on the exon region (rs10509681 variant) and the 3-UTR region (rs1058932 variant), in relation to PCOS risk. Blood samples were collected from 24 women with PCOS and 24 healthy controls (ages 20-40) at Al-Batool Teaching Hospital, Diyala Governorate, Iraq. Sequencing analysis identified three genotypes (GG, GA, AA) at the rs1058932 variant, with odds ratios of 0.82, 1.50, and 0.32, respectively. The GA genotype was identified as a potential risk factor for PCOS, while GG and AA were protective. In the exon region (rs10509681), two genotypes (TT, TC) were found, with the TT genotype showing an odds ratio of 3.29, suggesting an increased risk, while the TC genotype had an odds ratio of 0.32, indicating a protective role. Overall, the distribution of genotypes and allele frequencies showed no significant differences between groups according to Fisher's probability and Hardy-Weinberg equilibrium. The study highlights the potential involvement of CYP2C8 polymorphisms in PCOS risk, emphasizing the need for further large-scale investigations. [ABSTRACT FROM AUTHOR]

Introduction: Human genome consists of the three billion base pairs that has about one percent of genetic variation from one person to another، which determines physical، psychological، and susceptibility to diseases. Among the types of genetic diversity, single nucleotide polymorphisms are one of the most important genetic differences between two people. Single nucleotide polymorphism variation is located in the promoter region, exons، introns، untranslated regions and other Deoxyribonucleic acid (DNA) regions. While variation in the exon region can change susceptibility to diseases depending on whether it changes the protein structure or affects translation kinetics. Diversity in the promoter region can affect the interaction of genetic and epigenetic elements. Also، variation in the promoter region can affect the DNA methylation status. Polymorphic variation in the intron region can affect Messenger Ribonucleic acid splicing and the function of cis-regulatory elements. Polymorphic variation in the 5' Untranslated region، region causes a change in translation efficiency,، while a change in the 3' Untranslated region binds micro Ribonucleic acids to their position then affects the effects. In some cases، variations in Transfer Ribonucleic acid (tRNA) and Ribosomal ribonucleic acid (rRNA) affect the function of these regulatory cis elements. Conclusion: From a clinical point of view, a deep knowledge of this type of genetic variation can help the treatment process, manage patients and understand the prognosis based on these SNPs. Private or personalized medicine is also fundamentally based on genetic diversity. In this article, it was reviewed the types of single nucleotide genetic variation and presented examples of types of cancer, neurological and immunological diseases.

Protein folding and evolution are intimately linked phenomena. Here, we revisit the concept of exons as potential protein folding modules across a set of 38 abundant and conserved protein families. Taking advantage of genomic exon-intron organization and extensive protein sequence data, we explore exon boundary conservation and assess the foldon-like behavior of exons using energy landscape theoretic measurements. We found deviations in the exon size distribution from exponential decay indicating selection in evolution. We show that when taken together there is a pronounced tendency to independent foldability for segments corresponding to the more conserved exons, supporting the idea of exon-foldon correspondence. While 45% of the families follow this general trend when analyzed individually, there are some families for which other stronger functional determinants, such as preserving frustrated active sites, may be acting. We further develop a systematic partitioning of protein domains using exon boundary hotspots, showing that minimal common exons correspond with uninterrupted alpha and/or beta elements for the majority of the families but not for all of them. [ABSTRACT FROM AUTHOR]

Previously, we showed that the germ cell-specific nuclear protein RBMXL2 represses cryptic splicing patterns during meiosis and is required for male fertility (Ehrmann et al., 2019). Here, we show that in somatic cells the similar yet ubiquitously expressed RBMX protein has similar functions. RBMX regulates a distinct class of exons that exceed the median human exon size. RBMX protein-RNA interactions are enriched within ultra-long exons, particularly within genes involved in genome stability, and repress the selection of cryptic splice sites that would compromise gene function. The RBMX gene is silenced during male meiosis due to sex chromosome inactivation. To test whether RBMXL2 might replace the function of RBMX during meiosis we induced expression of RBMXL2 and the more distantly related RBMY protein in somatic cells, finding each could rescue aberrant patterns of RNA processing caused by RBMX depletion. The C-terminal disordered domain of RBMXL2 is sufficient to rescue proper splicing control after RBMX depletion. Our data indicate that RBMX and RBMXL2 have parallel roles in somatic tissues and the germline that must have been conserved for at least 200 million years of mammalian evolution. We propose RBMX family proteins are particularly important for the splicing inclusion of some ultra-long exons with increased intrinsic susceptibility to cryptic splice site selection.

NKG2D is a natural killer cell activating receptor recognising ligands on infected or tumorigenic cells, leading to their cytolysis. There are eight known genes encoding NKG2D ligands: MICA, MICB and ULBP1‐6. MICA and MICB are highly polymorphic and well characterised, whilst ULBP ligands are less polymorphic and the functional implication of their diversity is not well understood. Using International HLA and Immunogenetics Workshop (IHIW) cell line DNA, we previously characterised alleles of the RAET1E gene (encoding ULBP4 proteins), including the 5′ UTR promoter region and exons 1–3. We found 11 promoter haplotypes associating with alleles based on exons 1–3, revealing 19 alleles overall. The current study extends this analysis using 87 individual DNA samples from IHIW cell lines or cord blood to include RAET1E exon 4 and the 3′ UTR, as polymorphism in these regions have not been previously investigated. We found two novel exon 4 polymorphisms encoding amino acid substitutions altering the transmembrane domain. An amino acid substitution at residue 233 was unique to the RAET1E*008 allele whereas the substitution at residue 237 was shared between groups of alleles. Additionally, four haplotypes were found based on 3′ UTR sequences, which were unique to certain alleles or shared with allele groups based on exons 1–4 polymorphisms. Furthermore, putative microRNAs were identified that may interact with these polymorphic sites, repressing transcription and potentially affecting expression levels. [ABSTRACT FROM AUTHOR]

The effect of DNA methylation on the regulation of gene expression has been extensively discussed in the literature. However, the potential association between DNA methylation and alternative splicing is not understood well. In this study, we integrated multiple omics data types from The Cancer Genome Atlas (TCGA) and systematically examined the relationship between DNA methylation and alternative splicing. Using the methylation data and exon expression data, we identified many CpG sites significantly associated with exon expression in various types of cancers. We further observed that the direction and strength of significant CpG-exon correlation tended to be consistent across different cancer contexts, indicating that some CpG-exon correlation patterns reflect fundamental biological mechanisms that transcend tissue- and cancer- types. We also discovered that CpG sites correlated with exon expressions were more likely to be associated with patient survival outcomes compared to CpG sites that did not correlate with exon expressions. Furthermore, we found that CpG sites were more strongly correlated with exon expression than expression of isoforms harboring the corresponding exons. This observation suggests that a major effect of CpG methylation on alternative splicing may be related to the inclusion or exclusion of exons, which subsequently impacts the relative usage of various isoforms. Overall, our study revealed correlation patterns between DNA methylation and alternative splicing, which provides new insights into the role of methylation in the transcriptional process.

With declining biodiversity worldwide, a better understanding of species diversity and their relationships is imperative for conservation and management efforts. Marine sponges are species‐rich ecological key players on coral reefs, but their species diversity is still poorly understood. This is particularly true for the demosponge order Haplosclerida, whose systematic relationships are contentious due to the incongruencies between morphological and molecular phylogenetic hypotheses. The single gene markers applied in previous studies did not resolve these discrepancies. Hence, there is a high need for a genome‐wide approach to derive a phylogenetically robust classification and understand this group's evolutionary relationships. To this end, we developed a target enrichment‐based multilocus probe assay for the order Haplosclerida using transcriptomic data. This probe assay consists of 20,000 enrichment probes targeting 2956 ultraconserved elements in coding (i.e. exon) regions across the genome and was tested on 26 haplosclerid specimens from the Red Sea. Our target‐enrichment approach correctly placed our samples in a well‐supported phylogeny, in agreement with previous haplosclerid molecular phylogenies. Our results demonstrate the applicability of high‐resolution genomic methods in a systematically complex marine invertebrate group and provide a promising approach for robust phylogenies of Haplosclerida. Subsequently, this will lead to biologically unambiguous taxonomic revisions, better interpretations of biological and ecological observations and new avenues for applied research, conservation and managing declining marine diversity. [ABSTRACT FROM AUTHOR]

In non-small cell lung cancer (NSCLC) with classical EGFR mutation, EGFR tyrosine kinase inhibitors (TKIs) produce better results than platinum-based chemotherapy. However, therapeutic efficacy is quite different in patients with EGFR exon 20 insertion mutations (ex20ins) versus common mutations. Patients with ex20ins mutations are insensitive to EGFR-TKIs and have poor prognosis. It is important to know the demographic and clinical characteristics in this group of patients and the prevalence in our region. Methodology: retrospective, single institution, case series review of patients with non-small cell lung cancer with exon 20 insertion mutations from 2017-2023. Patients had received first-line therapy for advanced disease and had imaging studies to assess response. Demographics, characteristics, and treatment of each patient were recorded. Treatment response was assessed using RECIST v1.1 criteria and overall survival was calculated using the Kaplan Meier method. Results: Among the 15 patients identified with non-small cell lung cancer with exon 20 insertion mutations at our institution, the incidence for the mutation was 1.5%. The mean age was 60 years, 46.7% were women, and the incidence of the mutation was 1.5%. The average age was 60 years, 46.7% were women, 14 patients were Hispanic and 1 patient was Asian, only 3 patients had a history of smoking. Forty percent of the patients had an Eastern Cooperative Oncology Group (ECOG) functional score of 2. The histologic subtype was adenocarcinoma in all cases. Of the 13 (86.7%) patients who received first-line treatment had evaluable scans to determine response, 11 progressed, 1 patient had stable disease, and 1 patient had a partial response. The median overall survival (OS) was 5 months. Conclusions: Patients with exon 20 insertion mutations have resistance to tyrosine kinase inhibitors, which confers a worse prognosis. It is vital to know in our region the incidence of the mutation and patient characteristics to provide timely diagnosis and treatment. Our results provide an important context for the development of new therapies that can be approved in the first line of treatment and not in subsequent lines. [ABSTRACT FROM AUTHOR]

Background: Wilson disease (WD) is a genetic disorder (autosomal recessive) that affects copper metabolism. A favorable prognosis for WD can be achieved with early diagnosis and treatment. It is also strongly advised to conduct a family screening.Objective: To find the relationship between genotype and phenotype to facilitate the diagnosis of the disease as well as using modern methods in diagnosing WD.Methods: This study included nine WD patients and fifteen healthy participants. Members of patients with WD and healthy members provided whole blood. Blood DNA was extracted, and Exon 14 was amplified using specific primers using polymerase chain reaction (PCR). The results of the PCR products were aligned to the published human genome database using the BLAST tool.Results: Three different variations have been recorded as a result of the experiment. All of the changes point to a deficiency in the ATP7B protein, which has been identified as a cause of WD.Conclusions: The ATP7B gene mutation spectrum in Iraqi patients has been enhanced as a result of our research, and this information could be used to develop gene therapy and clinical/prenatal diagnosis to prevent WD in Iraq.

Alternative splicing (AS) produces the different mRNA splicing bodies, which are then translated into multiple protein isoforms and participate in various biological functions. With a deeper understanding of alternative splicing through the study of transcriptomes using high-throughput sequencing-based methods, the correlation between aberrant AS and diseases triggered a great concern, especially abnormal AS and cancer. Medulloblastoma (MB) is an intracranial tumor in children. Sonic hedgehog MB (SHH-MB) accounted for approximately 30% of MB, which is associated with the activation of SHH signaling. Growing evidence shows that aberrant AS is closely related to the tumorigenesis of MB. Here, we briefly introduced the AS and its mechanism. Next, we described canonical/noncanonical hedgehog signaling and its correlation with MB. The main description focused on AS of various regulators in canonical hedgehog signaling in MB. In addition, we also described AS of various regulators in noncanonical hedgehog signaling. Meanwhile, activated hedgehog signaling also induces AS in MB. Then, we pointed out that aberrant AS of hedgehog signaling is associated with different MB subgroups. Finally, we summarized the therapeutic applications of targeted AS in cancer treatment. In summary, further understanding of AS in SHH-MB could develop therapeutic targets for splicing factors which may be a novel therapeutic strategy.

Neuroblastoma is a childhood cancer characterized by the formation of tumors derived from neuroblasts. Identifying the genetic mutations underlying neuroblastoma for genetic counseling and early diagnosis is essential. Thus, this study aimed to screen for pathogenic gene variants within a neuroblastoma family, aiming to contribute to genetic counseling practices. Clinical data was collected from a family affected by neuroblastoma, and peripheral blood DNA samples were obtained from all family members. A combination of whole-exome sequencing and Sanger sequencing was utilized to detect potential gene mutations. Proband 1 and her sister (Proband 2) were diagnosed with neuroblastoma, while their parents and siblings were unaffected. The analysis revealed a novel missense mutation, c.422G > A (p.Arg141Gln), in the PHOX2B gene, which was inherited from the mother. Notably, this mutation represents a previously unreported variant within the PHOX2B gene. Detecting the missense mutation c.422G > A (p.Arg141Gln) in the PHOX2B gene implies its potential pathogenic role within this neuroblastoma family. This finding widens the range of mutations observed in the PHOX2B gene and has important implications for early neuroblastoma diagnosis within this family.

Plants have an intrinsic defense mechanism to defend themselves from different pathogens and activate suitable genetic mechanisms inside the cells via proteins. These proteins are encoded by a class of defense-related genes known as "R-genes". Nucleotide-binding site—leucine-rich repeats (NBS-LRRs) proteins recognize the pathogens directly or indirectly and activate downstream signaling pathways, which activate defense response. In the present study, the detailed analysis of NBS-LRR genes in mungbean (Vigna radiata) and their expression in two mungbean yellow mosaic India virus (MYMIV)-resistant wild Vigna accessions, PRR 2008-2 (V. umbellata) and TCR-20 (V. glabrescens), have been studied. Total of 87 VrNBS proteins were identified in mungbean genome and their subsequent classification and characterization were done. The expression of VrNBS-LRR genes in the wild non-progenitor Vigna species revealed that the MYMIV resistance in both the species follows different pathways. Therefore, the present study demonstrated the expression of VrNBS genes in wild Vigna background. The informations generated in present study will provide a valuable resource. The study also gives a clue for utilizing wild Vigna gene pool for improving MYMIV resistance in mungbean. [ABSTRACT FROM AUTHOR]

The present study was conducted on the MHC class I (BoLA-A/BuLA-A) gene in Sahiwal, Jersey, Hariana, and Tharparkar breeds of cattle and Murrah, Mehsana, and Bhadawari breeds of buffalo to study the polymorphism. Exons 7–8 of the MHC class I gene was first characterized for polymorphism study in buffalo and the results reveal that this gene has a higher level of nucleotide changes than the cattle. Genes were investigated for polymorphisms in 285 animals of cattle and buffalo breeds. Molecular characterization of the MHC class I (BoLa-A/Bula-A) gene reveals a higher degree of polymorphism at the nucleotide level in cattle and buffalo. Results revealed this region has a higher level of polymorphisms in buffalo as campared to the cattle. Alul restriction patterns were monomorphic except for three different patterns but it was able to illustrate the differences in buffalo and cattle. SSCP analysis of exons 7–8 showed remarkable differences in cattle and buffalo. Sequence analysis revealed more closeness of Murrah breed with crossbred and indigenous cattle than Holstein Friesian. Exon 8 had more deletion and stop codon as compared to exon 7. The investigation confirmed that MHC class I BoLa-A/Bula-A exons 7–8 is highly polymorphic in buffalo as compared to cattle. [ABSTRACT FROM AUTHOR]

Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder characterized by the production of autoantibodies against the thyroid gland. Different studies have shown that several genes may be associated with HT, which explains why patients often have family members with thyroiditis or other autoimmune diseases. The aim of this case-control study was to evaluate the correlation between polymorphisms at the level of exon 1 from the CTLA-4 gene and the susceptibility to developing HT. In this study, we found that there is no statistically significant association between the polymorphism rs231775 (A22G in exon 1) of the CTLA-4 gene and a genetic predisposition to HT. In contrast, a strong association was discovered for the first time between C55A in exon 1 of the CTLA-4 gene and HT. Our findings suggest that there is a genetic relationship between the CTLA-4 (+55A/C) genotype and the seropositivity against thyroid autoantigens, such as anti-thyroid peroxidase (ATPO) and anti-thyroglobulin antibodies (ATG). [ABSTRACT FROM AUTHOR]

Are there any differences between conjoined twin fetuses at the molecular level? Skin tissues were collected from thoracopagus conjoined twins at 15+4 weeks of gestation. The skin tissues were collected from the thigh side of conjoined twins after the abortion procedure. All specimens were obtained after written informed patient consent and were fully anonymized. All relevant ethical regulations were followed. Every specimen underwent multiomics sequencing analysis to determine associations among the DNA methylome, transcriptome and mutations in the exon regions in the conjoined twins. The global methylation pattern was similar in the two fetuses of conjoined twins, while significant differences were seen in local regions such as CpG islands (P = 0.026), enhancers (P < 0.001) and various repetitive elements (P < 0.05), which showed significant differences. The conjoined twins also differed in genes related to growth and development, cellular component morphogenesis and cellular stress, both in terms of DNA methylation levels and gene expression levels. Exon data analysis revealed that the common mutations in conjoined twins mainly occurred in neural development, lipid metabolism and microtubule morphogenesis. Specific mutations were associated with cellular component biosynthesis, behaviour and germ cell development. Conjoined twins were similar to each other globally, but there were significant differences related to growth and development, cellular component morphogenesis and cellular stress. The current study reveals the molecular features of conjoined twins for the first time, laying the foundation for future exploration of the mechanism of conjoined twins. [ABSTRACT FROM AUTHOR]

Abstract The effect of DNA methylation on the regulation of gene expression has been extensively discussed in the literature. However, the potential association between DNA methylation and alternative splicing is not understood well. In this study, we integrated multiple omics data types from The Cancer Genome Atlas (TCGA) and systematically examined the relationship between DNA methylation and alternative splicing. Using the methylation data and exon expression data, we identified many CpG sites significantly associated with exon expression in various types of cancers. We further observed that the direction and strength of significant CpG-exon correlation tended to be consistent across different cancer contexts, indicating that some CpG-exon correlation patterns reflect fundamental biological mechanisms that transcend tissue- and cancer- types. We also discovered that CpG sites correlated with exon expressions were more likely to be associated with patient survival outcomes compared to CpG sites that did not correlate with exon expressions. Furthermore, we found that CpG sites were more strongly correlated with exon expression than expression of isoforms harboring the corresponding exons. This observation suggests that a major effect of CpG methylation on alternative splicing may be related to the inclusion or exclusion of exons, which subsequently impacts the relative usage of various isoforms. Overall, our study revealed correlation patterns between DNA methylation and alternative splicing, which provides new insights into the role of methylation in the transcriptional process.

The aim of this study was to evaluate the association between gene polymorphisms (SNPs) and mastitis indicators and their relationship with milk production profitability in dairy herd. A functional analysis was also performed of five genes containing the studied SNPs and those located close by. DNA was isolated from the hair bulb of 320 dairy cows kept in three herds and SNP-microarray analysis was performed. The data on 299 cows was subjected to final statistical analysis using AI-REML method with one-trait repeatability test-day animal model and pedigree information using the DMU4 package. Five from 35 SNPs significantly associated with mastitis indicators or production traits and located within a gene or no more than 500,000 nucleotides from the gene were selected for the functional and economic analysis. A questionnaire was also developed to collect associated economic data of 219 cows from three herds, such as the value of milk production and direct costs incurred over three years; this allowed the gross margin, direct profitability index and direct costs incurred to produce one liter of milk to be determined, among others. None of the five studied SNPs were related to protein content. The rs110785912(T/A), found near CXCR4, and rs136813430(T/C), located in the TLR4 gene exon, were associated with lnSCC, while rs110455063(C/G), located near IGF-I, was associated with milk yield, fat and total solid contents. rs109421300(T/C), associated with fat/protein content ratio, as well as fat and total solid content, is located in the DGAT1 gene intron. rs41587003(A/C), located in the DLG2 gene intron, was associated with lactose content. The economic analysis revealed differences between the variants of the three tested SNPs. The T/C variant of the rs136813430(T/C) SNP was characterized by the highest gross margin, the highest direct profitability index and the lowest costs incurred to produce 1 liter of milk. The T/A variant of rs110785912(T/A) was related to low lnSC and was characterized by the highest direct profitability index. In turn, the C/C variant of the rs41587003(A/C) was related to the lowest level of lactose and the highest costs of milk production. It appears that rs136813430(T/C) may be the most promising of the tested SNPs for increasing the profitability of milk production. To our knowledge, it is the first effort to assess directly a correlation between the DNA polymorphism and economic output of a dairy enterprise. [ABSTRACT FROM AUTHOR]

(1) Hematological malignancies are characterized by an immortalization, uncontrolled proliferation of blood cells and their differentiation block, followed by the loss of function. The primary goal in the treatment of leukemias is the elimination of rapidly proliferating leukemic cells (named blasts). However, chemotherapy, which removes proliferating blasts, also prevents the remaining immune cells from being activated. Acute leukemias affect elderly people, who are often not fit to survive aggressive chemotherapy. Therefore, there is a need of milder treatment, named differentiation therapy, which might simulate the immune system of the patient. 1,25-Dihydroxyvitamin D, or low-calcemic analogs of this compound, were proposed as supporting therapy in acute leukemias. (2) Bone marrow blasts from patients with hematological malignancies, and leukocytes from healthy volunteers were ex vivo exposed to 1,25-dihydroxyvitamin D, and then their genomes and transcriptomes were investigated. (3) Our analysis indicates that 1,25-dihydroxyvitamin D regulates in blood cells predominantly genes involved in immune response, such as CAMP (cathelicidin antimicrobial peptide), CP (ceruloplasmin), CXCL9 (C-X-C motif chemokine ligand 9), CD14 (CD14 molecule) or VMO1 (vitelline membrane outer layer 1 homolog). This concerns blood cells from healthy people, as well as blasts from patients with hematological malignancies. In addition, in one patient, 1,25-dihydroxyvitamin D significantly downregulated transcription of genes responsible for cell division and immortalization. (4) In conclusion, the data presented in this paper suggest that addition of 1,25-dihydroxyvitamin D to the currently available treatments would stimulate immune system, inhibit proliferation and reduce immortal potential of blasts. [ABSTRACT FROM AUTHOR]

Abstract It has long been known that exons can serve as cis‐regulatory sequences, such as enhancers. However, the prevalence of such dual‐use of exons and how they evolve remain elusive. Based on our recently predicted, highly accurate large sets of cis‐regulatory module candidates (CRMCs) and non‐CRMCs in the human genome, we find that exonic transcription factor binding sites (TFBSs) occupy at least a third of the total exon lengths, and 96.7% of genes have exonic TFBSs. Both A/T and C/G in exonic TFBSs are more likely under evolutionary constraints than those in non‐CRMC exons. Exonic TFBSs in codons tend to encode loops rather than more critical helices and strands in protein structures, while exonic TFBSs in untranslated regions (UTRs) tend to avoid positions where known UTR‐related functions are located. Moreover, active exonic TFBSs tend to be in close physical proximity to distal promoters whose genes have elevated transcription levels. These results suggest that exonic TFBSs might be more prevalent than originally thought and likely in dual‐use. We proposed a parsimonious model that well explains the observed evolutionary behaviors of exonic TFBS as well as how a stretch of codons evolve into a TFBS. Key points There are more exonic regulatory sequences in the human genome than originally thought. Exonic transcription factor binding sites are more likely under negative selection or positive selection than counterpart nonregulatory sequences. Exonic transcription factor binding sites tend to be located in genome sequences that encode less critical loops in protein structures, or in less critical parts in 5′ and 3′ untranslated regions.

Most prokaryotic proteins consist of a single structural domain (SD) with little intrinsically disordered regions (IDRs) that by themselves do not adopt stable structures, whereas the typical eukaryotic protein comprises multiple SDs and IDRs. How eukaryotic proteins evolved to differ from prokaryotic proteins has not been fully elucidated. Here, we found that the longer the internal exons are, the more frequently they encode IDRs in eight eukaryotes including vertebrates, invertebrates, a fungus, and plants. Based on this observation, we propose the "small bang" model from the proteomic viewpoint: the protoeukaryotic genes had no introns and mostly encoded one SD each, but a majority of them were subsequently divided into multiple exons (step 1). Many exons unconstrained by SDs elongated to encode IDRs (step 2). The elongated exons encoding IDRs frequently facilitated the acquisition of multiple SDs to make the last common ancestor of eukaryotes (step 3). One prediction of the model is that long internal exons are mostly unconstrained exons. Analytical results of the eight eukaryotes are consistent with this prediction. In support of the model, we identified cases of internal exons that elongated after the rat–mouse divergence and discovered that the expanded sections are mostly in unconstrained exons and preferentially encode IDRs. The model also predicts that SDs followed by long internal exons tend to have other SDs downstream. This prediction was also verified in all the eukaryotic species analyzed. Our model accounts for the dichotomy between prokaryotic and eukaryotic proteins and proposes a selective advantage conferred by IDRs. [ABSTRACT FROM AUTHOR]

The MEFV (familial Mediterranean fever gene) researches were performed in the population of the Republic of Azerbaijan in 2016–2021. Seven mutations of the MEFV gene were identified in heterozygous, homozygous and compound homozygous conditions: R761H, M694I, M694V, V726A, R202Q, M680I and E148Q. The E148Q and R202Q mutations were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon 10 in the population of the Republic of Azerbaijan. The highest gene frequency of the MEFV gene examined in 42 patients was 42.85% in the M694V mutations. The second highest frequency was the R761H and the third most frequent mutation was V726A. According to world literature, five mutations, M694V, V726A, M694I, R202Q, M680I and E148Q, constitute 75.0% of all mutations found today. In our studies, these five mutations belong to the same group, and makes up 57.6% of the total mutations found. In order to prevent hereditary disease such as the familial Mediterranean fever (FMF) in the population of the Republic of Azerbaijan, it is planned to carry out prenatal diagnosis (PND) of the at-risk families.

Background and aims: In the phenylalanine hydroxylase (PAH) gene, various mutations are mainly responsible for phenylketonuria (PKU). After thalassemia, PKU is considered as the most common autosomal recessive disease among Iranian population. Therefore, identifying the mutations that cause the disease in this population is of great importance. This study aimed to identify exon 5 mutations of PAH gene in PKU patients from Golestan, the northern province of Iran, and compare these mutations with those onesa found by studies carried out in other parts of the country. Methods: During a one-year period, 25 unrelated PKU patients aged 1-23 years and from different parts of Golestan province were included in the study. Then, their genomic DNAs were extracted from their blood samples and PCR-sequencing method was used to identify the mutations. The sequencing results were analyzed using Chromas and CLC Main Workbench v3.5 software. Results: In this study, R158Q mutation was detected with a frequency of 6%. This mutation was homozygous in one PKU patient, but it was heterozygous in another one. These patients had cPKU phenotype. Conclusion: Evaluation of mutations proved to be a useful technique for molecular diagnosis of PKU and identification of disease carriers in the given population. Taking into account the fact that only one exon of PAH gene was explored in this study, however, it is recommended that further studies be conducted to investigate other exons in order for obtaining the complete mutation spectrum of this gene in PKU patients in Golestan province.

Background: Exons are an important part of genes. However, there has been no molecular marker technique based on single primer amplification developed for exons region. Results: A novel molecular marker technique called exon based amplified polymorphism (EBAP) which used single primer to perform the PCR was developed. Single primers were designed based on the rich GC bases in the exon region of genes. The single primer consists of filling sequence, intermediate core region sequence and selective bases sequence. The filling sequence has a total of six bases, which can be 2A and 2T or 3A and 3T. The intermediate core region sequence consists of eight bases, all of which are G and C, but at least 2G or 2C are required. The first of the three selective bases must be either A or T, and the second and third are arbitrary bases. Due to the principle of primer design, these single primers should be universal. We applied it to the DNA polymorphisms detection of maize, sugarcane, potato, cassava, cabbage, and peanut. The results showed that it detected more abundant DNA polymorphisms in the first five crops, but not in the cultivated peanut. In addition, different band patterns were obtained by amplifying peanut cDNA with different single primers. Conclusions: We have developed a novel and universal molecular marker technique. It is simple, fast and efficient. It does not require genomic sequence information. It can be widely used in germplasm identification, genetic diversity analysis, and molecular fingerprinting. How to cite: Xiong F, Liu J, Tang R, et al. Exon based amplified polymorphism (EBAP): A novel and universal molecular marker for plants. Electron J Biotechnol 2022;56. https://doi.org/10.1016/j.ejbt.2022.01.001.

Abstract Background Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline variants in the MEN1 gene located on chromosome 11q13. We found a Chinese woman who had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicion of gastrinoma. Case presentation The proband and her immediate family members underwent genetic detection. The results showed that two of the proband’s six relatives had the same variants as the proband, and her sister also had the typical symptoms of MEN1. However, the first- and second-time genetic detection results showed that they were homozygous variants, which did not conform to Mendelian inheritance laws. Multiplex ligation-dependent probe amplification (MLPA) was used to rule out homozygous variants caused by a deletion of gene fragments in the proband and her immediate family members. The MLPA results showed that the gene deletion was absent in the MEN1. The results from the third genetic detection (redesigned the primer) showed that they had a heterozygous variant. A new MEN1 germline variant [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found in this study. Conclusions This newly identified germline variant could improve the identification of clinical phenotypes and the early diagnosis of MEN1. Clinician should consider the present of situation that intron variant causing detection error. Re-designing the primers close to the variant site for gene detection could avoid this situation.

In this work, we analyzed 78 mutations in the actin protein that cause the disease nemaline myopathy. We analyzed how these mutations are distributed in important regions of the actin molecule (folding nucleus, core of the filament, amyloidogenic regions, disordered regions, regions involved in interaction with other proteins). It was found that 54 mutations (43 residues) fall into the folding nucleus (Ф ≥ 0.5), 11 mutations (10 residues) into the filament core, 14 mutations into the amyloidogenic regions (11 residues), 14 mutations (9 residues) in the unstructured regions, and 24 mutations (22 residues) in regions involved in interaction with other proteins. It was also found that the occurrence of single mutations G44V, V45F, T68I, P72R, K338I and S350L leads to the appearance of new amyloidogenic regions that are not present in native actin. The largest number of mutations (54 out of 78) occurs in the folding nucleus; these mutations are important for folding and therefore can affect the protein folding rate. We have shown that almost all of the considered mutations are associated with the structural characteristics of the actin molecule, and some of the residues we have considered have several important characteristics. [ABSTRACT FROM AUTHOR]

Animal species present relatively high levels of gene conservation, and yet they display a great variety of cell type and tissue phenotypes. These diverse phenotypes are mainly specified through differential gene usage, which relies on several mechanisms. Two of the most relevant mechanisms are regulated gene transcription, usually referred to as gene expression (rGE), and regulated alternative splicing (rAS). Several works have addressed how either rGE or rAS contributes to phenotypic diversity throughout evolution, but a back-to-back comparison between the two molecular mechanisms, specifically highlighting both their common regulatory principles and unique properties, is still missing. In this review, we propose an innovative framework for the unified comparison between rGE and rAS from different perspectives: the three-dimensional (3D)-evo space. We use the 3D-evo space to comprehensively (a) review the molecular basis of rGE and rAS (i.e., the molecular axis), (b) depict the tissue-specific phenotypes they contribute to (i.e., the tissue axis), and (c) describe the determinants that drive the evolution of rGE and rAS programs (i.e., the evolution axis). Finally, we unify the perspectives emerging from the three axes by discussing general trends and specific examples of rGE and rAS tissue program evolution. [ABSTRACT FROM AUTHOR]

The conventionally clear distinction between exons and introns in eukaryotic genes is actually blurred. To illustrate this point, consider sequences that are retained in mature mRNAs about 50% of the time: how should they be classified? Moreover, although it is clear that RNA splicing influences gene expression levels and is an integral part of interdependent cellular networks, introns continue to be regarded as accidental insertions; exogenous sequences whose evolutionary origin is independent of mRNA-associated processes and somewhat still elusive. Here, we present evidence that aids to resolve this disconnect between conventional views about introns and current knowledge about the role of RNA splicing in the eukaryotic cell. We first show that coding sequences flanked by cryptic splice sites are negatively selected on a genome-wide scale in Paramecium. Then, we exploit selection intensity to infer splicing-related evolutionary dynamics. Our analyses suggest that intron gain begins as a splicing error, involves a transient phase of alternative splicing, and is preferentially completed at the 5' end of genes, which through intron gain can become highly expressed. We conclude that relaxed selective constraints may promote biological complexity in Paramecium and that the relationship between exons and introns is fluid on an evolutionary scale. [ABSTRACT FROM AUTHOR]

Previously, we showed that the germ cell-specific nuclear protein RBMXL2 represses cryptic splicing patterns during meiosis and is required for male fertility (Ehrmann et al., 2019). Here, we show that in somatic cells the similar yet ubiquitously expressed RBMX protein has similar functions. RBMX regulates a distinct class of exons that exceed the median human exon size. RBMX protein-RNA interactions are enriched within ultra-long exons, particularly within genes involved in genome stability, and repress the selection of cryptic splice sites that would compromise gene function. The RBMX gene is silenced during male meiosis due to sex chromosome inactivation. To test whether RBMXL2 might replace the function of RBMX during meiosis we induced expression of RBMXL2 and the more distantly related RBMY protein in somatic cells, finding each could rescue aberrant patterns of RNA processing caused by RBMX depletion. The C-terminal disordered domain of RBMXL2 is sufficient to rescue proper splicing control after RBMX depletion. Our data indicate that RBMX and RBMXL2 have parallel roles in somatic tissues and the germline that must have been conserved for at least 200 million years of mammalian evolution. We propose RBMX family proteins are particularly important for the splicing inclusion of some ultra-long exons with increased intrinsic susceptibility to cryptic splice site selection., Competing Interests: CS, SL, SA, GH, CD, KC, MG, IY, KJ, MK, IE, GS, SC, JM, SW, YB, DE No competing interests declared, (© 2023, Siachisumo, Luzzi, Aldalaqan et al.)

Hashimoto’s thyroiditis (HT) is a chronic autoimmune disorder characterized by the production of autoantibodies against the thyroid gland. Different studies have shown that several genes may be associated with HT, which explains why patients often have family members with thyroiditis or other autoimmune diseases. The aim of this case-control study was to evaluate the correlation between polymorphisms at the level of exon 1 from the CTLA-4 gene and the susceptibility to developing HT. In this study, we found that there is no statistically significant association between the polymorphism rs231775 (A22G in exon 1) of the CTLA-4 gene and a genetic predisposition to HT. In contrast, a strong association was discovered for the first time between C55A in exon 1 of the CTLA-4 gene and HT. Our findings suggest that there is a genetic relationship between the CTLA-4 (+55A/C) genotype and the seropositivity against thyroid autoantigens, such as anti-thyroid peroxidase (ATPO) and anti-thyroglobulin antibodies (ATG).

• Engineering of sequence-specific alternative splicing modulators. • Robust exclusion of endogenous FAS exon 6 and inclusion of endogenous SMN2 exon 7. • Underscoring U1 snRNA as a candidate therapeutic and research tool. Alternative splicing accounts for a considerable portion of transcriptomic diversity, as most protein-coding genes are spliced into multiple mRNA isoforms. However, errors in splicing patterns can give rise to mis-splicing with pathological consequences, such as the congenital diseases familial dysautonomia, Duchenne muscular dystrophy, and spinal muscular atrophy. Small nuclear RNA (snRNA) components of the U snRNP family have been proposed as a therapeutic modality for the treatment of mis-splicing. U1 snRNAs offer great promise, with prior studies demonstrating in vivo efficacy, suggesting additional preclinical development is merited. Improvements in enabling technologies, including screening methodologies, gene delivery vectors, and relevant considerations from gene editing approaches justify further advancement of U1 snRNA as a therapeutic and research tool. With the goal of providing a user-friendly protocol, we compile and demonstrate a methodological toolkit for sequence-specific targeted perturbation of alternatively spliced pre-mRNA with engineered U1 snRNAs. We observe robust modulation of endogenous pre-mRNA transcripts targeted in two contrasting splicing contexts, SMN2 exon 7 and FAS exon 6, exhibiting the utility and applicability of engineered U1 snRNA to both inclusion and exclusion of targeted exons. We anticipate that these demonstrations will contribute to the usability of U1 snRNA in investigating splicing modulation in eukaryotic cells, increasing accessibility to the broader research community. [ABSTRACT FROM AUTHOR]

Camels are semi-ruminant placental mammals, classified as two-toed, padded-footed mammals, and belong to the family Camelidae, which includes the one-humped camels (Camelus dromedaries), and the two-humped camels (Camelus bactrianus), llama, Alpaca, Vicuna, and Guanaco. The study used 50 Iraqi single-humped camel females who belonged to private fields in the AL-Furat AL-Awsat region, which involved three Iraqi cities (Babylon, Diwaniyah, and Muthanna). All the Biotechnological and Molecular Genetics analyses were performed in the Altakadum Laboratory, Baghdad, in order to determine the genotypes and their distribution ratios for the POU1F1 gene and the relationship of the Polymorphism of the gene with some productive traits, growth characteristics (weight and body dimensions) and blood biochemical parameters of animals. The mutation 225131 was in the second exon region, in which there was a change in the amino acid C.49 CAA>CAC Gln>His. Three genotypes were discovered in this mutation in the second studied piece, which included the region of the first intron and the second exon, with a length of 777 base pairs using DNA sequencing technology. The results indicated that there were highly significant differences (P=0.01) in the distribution ratios of the genotypes resulting from the mutation. The results also showed a significant relationship between these genotypes with somebody dimensions, as there was a significant superiority (P=0.05) for individuals with mutant CC genotype over the wild AA and hetero AC genotypes in each of the traits, body height from the front (220.66±1.76, 215.12±0.92, 212.80 ±2.33) cm and body length (186.66±1.20, 179.47±1.10, 170.00±4.96) cm and head length (55.00±2.08, 50.78±0.46, 51.20 ±1.31) cm for the mutant, wild and hetero, genotypes respectively. Concerning the characteristics of the length of the milking season, daily and total milk production, and its chemical components, there was no significant relationship between the genotypes resulting from the studied mutation. [ABSTRACT FROM AUTHOR]

In this review, we explore recombination in two very different virus families that have become major threats to human health. The Herpesviridae are a large family of pathogenic double-stranded DNA viruses involved in a range of diseases affecting both people and animals. Coronaviridae are positive-strand RNA viruses (CoVs) that have also become major threats to global health and economic stability, especially in the last two decades. Despite many differences, such as the make-up of their genetic material (DNA vs. RNA) and overall mechanisms of genome replication, both human herpes viruses (HHVs) and CoVs have evolved to rely heavily on recombination for viral genome replication, adaptation to new hosts and evasion of host immune regulation. In this review, we will focus on the roles of three viral exonucleases: two HHV exonucleases (alkaline nuclease and PolExo) and one CoV exonuclease (ExoN). We will review the roles of these three nucleases in their respective life cycles and discuss the state of drug discovery efforts against these targets. [ABSTRACT FROM AUTHOR]

Objetivo. Determinar la influencia de la aplicación de gonadotropina coriónica equina (eCG) y la presencia del exón 2 del gen GDF9 en variables reproductivas en ovejas de la raza Katahdin en época de transición. Materiales y métodos. Se utilizaron 63 ovejas con edad y peso promedio de 2.83±0.89 años y 45.32±5.44 kg, respectivamente. Se usó un arreglo factorial 2x2 bajo un diseño completamente al azar, donde los factores y niveles fueron: la ausencia o presencia del exón 2 del gen GDF9 y la aplicación o no de la hormona eCG en el protocolo de sincronización. Resultados. La aplicación de eCG mostró un efecto significativo favorable en el comportamiento reproductivo de las ovejas, no así para la presencia del exón 2 del gen GDF9. Los tratamientos T2 y T4 fueron superiores en las variables % de gestación, % de parición, fecundidad y prolificidad con respecto a T1 y T3. La mejor respuesta reproductiva se obtuvo con la aplicación de eCG independiente de la presencia o ausencia del gen. Conclusiones. Este estudio muestra evidencia de la nula interacción del exón 2 del gen GDF9 y la eCG para mejorar el rendimiento reproductivo de ovejas. Se recomienda la aplicación de eCG en protocolos de sincronización de estros para ovejas de la raza Kathadin en época de transición. Frente a los pocos reportes genómicos en la raza, se muestra evidencia de la necesidad para realizar otras investigaciones de las variantes genéticas y su relación con la reproducción en ovejas.

Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare inherited monogenic autoimmune disease characterized by the presence of at least two of three following major clinical features: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Mutations in autoimmune regulator (AIRE) gene have been found to contribute to APS-1. In the present study, we reported a 36-years-old male APS-1 patient who presented with hypoparathyroidism and Addison’s disease. The proband underwent complete clinical examinations and mutation screening was performed by Sanger sequencing on AIRE gene. A novel homozygous mutation in exon 9 of the AIRE gene (c.1024C>T) was identified. Based on sequencing findings, HEK293T cell-based assays were conducted to analyze the subcellular localization and mutant transcript processing. Our results revealed that p.Q342X mutant localized in nuclear speckles and exerted a dominant-negative effect on wildtype AIRE function. We reported the c.1024C>T mutation of AIRE gene for the first time, which enriched the AIRE mutation database and contributed to further understanding of APS-1.

Machine learning methods played a major role in improving the accuracy of predictions and classification of DNA (Deoxyribonucleic Acid) and protein sequences. In eukaryotes, Splice-site identification and prediction is though not a straightforward job because of numerous false positives. To solve this problem, here, in this paper, we represent a bidirectional Long Short Term Memory (LSTM) Recurrent Neural Network (RNN) based deep learning model that has been developed to identify and predict the splice-sites for the prediction of exons from eukaryotic DNA sequences. During the splicing mechanism of the primary mRNA transcript, the introns, the non-coding region of the gene are spliced out and the exons, the coding region of the gene are joined. This bidirectional LSTM-RNN model uses the intron features that start with splice site donor (GT) and end with splice site acceptor (AG) in order of its length constraints. The model has been improved by increasing the number of epochs while training. This designed model achieved a maximum accuracy of 95.5%. This model is compatible with huge sequential data such as the complete genome.

• To make use of the splice-junction dataset constituting 60 nucleotides as 180 binary variables in classifying three binary indicator variables. • The purpose of this study is to classify three binary combinations of EI, IE, and none with M−LSTM based on three modified gates: a blocked gate, a divergent gate, and a merge gate. • The efficiency of the proposed model is evaluated based on probabilistic metrics such as recall, F1-score, precision, and accuracy with appropriate insights into the dataset. Bioinformatics is a contemporary interdisciplinary area focused on analyzing the growing number of genome sequences. Gene variants are differences in DNA sequences among individuals within a population. Splice site recognition is a crucial step in the process of gene expression, where the coding sequences of genes are joined together to form mature messenger RNA (mRNA). These genetic variants that disrupt genes are believed to be the primary reason for neuro-developmental disorders like ASD (Autism Spectrum Disorder) is a neuro-developmental disorder that is diagnosed in individuals, families, and society and occurs as the developmental delay in one among the hundred genes that are associated with these disorders. Missense variants, premature stop codons, or deletions alter both the quality and quantity of encoded proteins. Predicting genes within exons and introns presents main challenges, such as dealing with sequencing errors, short reads, incomplete genes, overlapping, and more. Although many traditional techniques have been utilized in creating an exon prediction system, the primary challenge lies in accurately identifying the length and spliced strand location classification of exons in conjunction with introns. From now on, the suggested approach utilizes a Deep Learning algorithm to analyze intricate and extensive genomic datasets. M−LSTM is utilized to categorize three binary combinations (EI as 1, IE as 2, and none as 3) using spliced DNA strands. The M−LSTM system is able to sequence extensive datasets, ensuring that long information can be stored without any impact on the current input or output. This enables it to recognize and address long-term connections and problems with rapidly increasing gradients. The proposed model is compared internally with Naïve Bayes and Random Forest to assess its efficacy. Additionally, the proposed model's performance is forecasted by utilizing probabilistic parameters like recall, F1-score, precision, and accuracy to assess the effectiveness of the proposed system. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. While the development of vaccines and the emergence of antiviral therapeutics is promising, alternative strategies to combat COVID-19 (and potential future pandemics) remain an unmet need. Coronaviruses feature a unique mechanism that may present opportunities for therapeutic intervention: the RNA polymerase complex of coronaviruses is distinct in its ability to proofread and remove mismatched nucleotides during genome replication and transcription. The proofreading activity has been linked to the exonuclease (ExoN) activity of non-structural protein 14 (NSP14). Here, we review the role of NSP14, and other NSPs, in SARS-CoV-2 replication and describe the assays that have been developed to assess the ExoN function. We also review the nucleoside analogs and non-nucleoside inhibitors known to interfere with the proofreading activity of NSP14. Although not yet validated, the potential use of non-nucleoside proofreading inhibitors in combination with chain-terminating nucleosides may be a promising avenue for the development of anti-CoV agents. [ABSTRACT FROM AUTHOR]

Deep Learning techniques (DL) significantly improved the accuracy of predictions and classifications of deoxyribonucleic acid (DNA). On the other hand, identifying and predicting splice sites in eukaryotes is difficult due to many erroneous discoveries. To address this issue, we propose a deep learning model for recognizing and anticipating splice sites in eukaryotic DNA sequences based on a bidirectional Long Short-Term Memory (LSTM) Recurrent Neural Network (RNN) and Gated recurrent unit (GRU). The non-coding introns of the gene are spliced out, and the coding exons are joined during the splicing of the original mRNA transcript. This bidirectional LSTM-RNN-GRU model incorporates intron features in order of their length constraints, beginning with splice site donor (GT) and ending with splice site acceptor (AG). The performance of the model improves as the number of training epochs grows. The best level of accuracy for this model is 96.1 percent. [ABSTRACT FROM AUTHOR]

Background: Amniocentesis was performed on a pregnant woman with a deletion of exon 45 of the Duchenne Muscular Dystrophy (DMD) gene. Methods: Fetal Xp21.1 (31944831-32030363) x 0 was found by chromosome microarray analysis (CMA), i.e., 0.086 Mb hemizygote deletion was detected in the Xp21.1 region of the fetal X chromosome, which contained exon 45 of the DMD gene. Results: The results verified by MLPA were consistent with those of CMA, which indicated that CMA was accurate in a single exon deletion in this fetus. This case suggests that CMA may become an essential method for the prenatal diagnosis of a fetus with DMD gene deletion/duplication. Conclusions: It can routinely detect chromosome copy number variation and analyze DMD diseases caused by exon duplication or deletion, which is enormously significant for new DMD exon deletion or duplication. [ABSTRACT FROM AUTHOR]

Background: The aromatic rice cultivars sometimes show variation in aroma when they are grown in regions other than their normal traditional growing regions. An early maturing selection from a Kerala aromatic local landrace with short grains, named 'Biriyanicheera', when grown in normal tropical conditions was sufficiently fragrant. The present study focused on the analysis of aroma in 'Biriyanicheera' rice genotype through molecular methods. Methods and results: The seeds of two aromatic rice varieties viz., Biriyanicheera and Gandhakasala (aromatic check) along with one non-aromatic rice variety Triveni (control) were used for the study. The BADH2 gene was amplified in all the three rice varieties. Upon sequencing the amplified PCR products of genomic DNA, the mutation in BADH2 gene was detected. The sequencing results of aromatic rice varieties revealed the presence of 8 base pair mutation in exon 7 in Biriyanicheera and Gandhakasaala, whereas this mutation was absent in the non-aromatic variety Triveni. Conclusions: Aroma production in Biriyanicheera variety is observed to be due to the similar mutation in BADH2 gene as that of the popular scented rice Basmati. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline variants in the MEN1 gene located on chromosome 11q13. We found a Chinese woman who had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicion of gastrinoma. Case presentation: The proband and her immediate family members underwent genetic detection. The results showed that two of the proband's six relatives had the same variants as the proband, and her sister also had the typical symptoms of MEN1. However, the first- and second-time genetic detection results showed that they were homozygous variants, which did not conform to Mendelian inheritance laws. Multiplex ligation-dependent probe amplification (MLPA) was used to rule out homozygous variants caused by a deletion of gene fragments in the proband and her immediate family members. The MLPA results showed that the gene deletion was absent in the MEN1. The results from the third genetic detection (redesigned the primer) showed that they had a heterozygous variant. A new MEN1 germline variant [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found in this study. Conclusions: This newly identified germline variant could improve the identification of clinical phenotypes and the early diagnosis of MEN1. Clinician should consider the present of situation that intron variant causing detection error. Re-designing the primers close to the variant site for gene detection could avoid this situation. [ABSTRACT FROM AUTHOR]

Background and aims: In the phenylalanine hydroxylase (PAH) gene, various mutations are mainly responsible for phenylketonuria (PKU). After thalassemia, PKU is considered as the most common autosomal recessive disease among Iranian population. Therefore, identifying the mutations that cause the disease in this population is of great importance. This study aimed to identify exon 5 mutations of PAH gene in PKU patients from Golestan, the northern province of Iran, and compare these mutations with those onesa found by studies carried out in other parts of the country. Methods: During a one-year period, 25 unrelated PKU patients aged 1-23 years and from different parts of Golestan province were included in the study. Then, their genomic DNAs were extracted from their blood samples and PCR-sequencing method was used to identify the mutations. The sequencing results were analyzed using Chromas and CLC Main Workbench v3.5 software. Results: In this study, R158Q mutation was detected with a frequency of 6%. This mutation was homozygous in one PKU patient, but it was heterozygous in another one. These patients had cPKU phenotype. Conclusion: Evaluation of mutations proved to be a useful technique for molecular diagnosis of PKU and identification of disease carriers in the given population. Taking into account the fact that only one exon of PAH gene was explored in this study, however, it is recommended that further studies be conducted to investigate other exons in order for obtaining the complete mutation spectrum of this gene in PKU patients in Golestan province. [ABSTRACT FROM AUTHOR]

Objective To investigate the genetic variation and inheritance of a child with 17α-hydroxylase/17，20- lyase deficiency（17OHD）. Methods A child was diagnosed with 17OHD，and the main clinical manifestations were bi‑ lateral inguinal mass and feminization of external genitalia pseudohermaphroditism. We extracted peripheral venous blood from the child，her parents and her elder brother. Whole-genome exon sequencing was performed by using High-Through‑ put Sequencing（HTS）technology to analyze the gene of the patient，her parents and her elder brother. Results A homo‑ zygous mutation c. 987delC（p. Tyr329fs）located in exon 6 of cytochrome P450c17 enzyme gene（CYP17A1 gene）was identified in the child. A heterozygous mutation c. 987delC（p. Tyr329fs）located in exon 6 of CYP17A1 gene on chromo‑ some 10 was identified in both her parents and her elder brother. Conclusions The child with 17OHD had a homozy‑ gous mutation c. 987delC（p. Tyr329fs）located in exon 6 of CYP17A1 gene on chromosome 10. Her parents and her elder brother had heterozygous mutation c. 987delC（p. Tyr329fs）located in exon 6 of CYP17A1 gene on chromosome 10. The exon mutation in patient with 17OHD was inherited from parents. [ABSTRACT FROM AUTHOR]

Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions. [ABSTRACT FROM AUTHOR]

Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.

The MEFV (familial Mediterranean fever gene) researches were performed in the population of the Republic of Azerbaijan in 2016–2021. Seven mutations of the MEFV gene were identified in heterozygous, homozygous and compound homozygous conditions: R761H, M694I, M694V, V726A, R202Q, M680I and E148Q. The E148Q and R202Q mutations were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon 10 in the population of the Republic of Azerbaijan. The highest gene frequency of the MEFV gene examined in 42 patients was 42.85% in the M694V mutations. The second highest frequency was the R761H and the third most frequent mutation was V726A. According to world literature, five mutations, M694V, V726A, M694I, R202Q, M680I and E148Q, constitute 75.0% of all mutations found today. In our studies, these five mutations belong to the same group, and makes up 57.6% of the total mutations found. In order to prevent hereditary disease such as the familial Mediterranean fever (FMF) in the population of the Republic of Azerbaijan, it is planned to carry out prenatal diagnosis (PND) of the at-risk families. [ABSTRACT FROM AUTHOR]