Porphobilinogen Deaminase Research Articles

Myocardial injury and heart failure biomarkers in acute intermittent porphyria

Abstract Background Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by the defect in the hydroxymethylbilane synthase gene, encoding the third enzyme in heme biosynthesis pathway. The main symptoms include abdominal pain, vomiting, paralysis, confusion. Exacerbation of AIP may manifest with elevation of blood pressure and tachycardia due to hyperactivity of sympathetic nervous system. Data regarding cardiac function in AIP are scarce. Purpose The aim of this study was to assess the myocardial injury and heart failure biomarkers during AIP exacerbations and remission. Methods This cohort prospective study encompassed patients at the age 18-65 years who had at least one exacerbation of AIP in their lifetime. Patients examined during the AIP exacerbations were reassessed in the remission phase. The concentrations of sodium, troponin T, CK-MB mass, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and metoxycatecholamines in blood were assessed. Blood pressure was measured with 24-hour ABPM. Echocardiography was performed according to the current recommendations. Results The total number of 70 patients with AIP were enrolled to the study (April 2019 - March 2023). We assessed 36 patients in both phases of disease, mean age 37 years (21-63), 75% females. The median of prior AIP exacerbations was 8. During the exacerbations a significant increase in the concentrations of NT-proBNP (250 [97 ; 501] vs. 89 [48 ; 140] pg/mL, p<0.001), metanephrine (49.0 [37.8 ; 61.2] vs. 41.4 [36.8 ; 53.3] pg/mL, p=0.009) and normetanephrine (169.8 [118.2 ; 327.2] vs. 93.2 [78.1 ; 120.9] pg/mL, p<0.001) was observed. Conversely, sodium concentrations decreased (136 [133 ; 140] vs. 140 [139 ; 142] mmol/L, p<0.001). There were no significant differences in the values of troponin (5.4 [4.0 ; 11.3] vs. 5.6 [3.7 ; 9.5] ng/L, p=0.445), CK-MB mass (1.88 [0.84 ; 2.64] vs. 1.21 [0.83 ; 2.80] ng/mL, p=0.80). In the acute phases of AIP the levels of NT-proBNP were correlated negatively with the values of sodium concentrations (r=-0.36, p=0.032) and positively with average systolic blood pressure (r=0.32, p=0.06). Echocardiography showed an increase in left ventricular (LV) mass indices in some patients hospitalized due to AIP symptoms. Sodium concentrations correlated negatively with these changes (r=-0.36, p=0.032). LV ejection fraction was slightly higher during AIP exacerbations. There were no significant differences in other parameters of LV systolic and diastolic function. Conclusions During acute intermittent porphyria (AIP) exacerbations there is an increase in the concentrations of NT-proBNP and catecholamines in blood. In most patients the levels of markers of myocardial injury, such as troponin and CK-MB mass, do not differ significantly between phases of disease. During AIP exacerbations some patients experience an increase in LV mass which may be associated with hyponatremia. In most cases cardiac function do not change significantly.Frequency of abnormal laboratory resultsResults of echocardiography

Low availability of haematin (hemin) in Pakistan

Madam, Acute Intermittent Porphyria (AIP) is an autosomal dominant disorder that results from a defect in the enzyme named porphobilinogen deaminase.1 It is symptomatic porphyria, involving the accumulation of porphyrins and porphyrin precursors due to impaired conversion in haeme synthesis. Acute Intermittent Porphyria is clinically characterized by acute episodes of multiple gastrointestinal and neurologic symptoms; during which the patient remains healthy between episodes.2 Acute Intermittent Porphyria episodes are commonly observed in post pubertal females. The most common symptoms include periodic abdominal pain, vomiting and hypertension followed by neurologic damage that leads to peripheral and autonomic neuropathies (mostly motor) and psychiatric manifestations.2 Hormonal cycle regulation may worsen porphyria, since its symptoms coincide with the menstrual cycle. Although positive response has been noted in hormonal suppression by gonadotropin releasing hormone agonists.3 Currently, the most widely used treatment is hemin, a form of haeme that can be given intravenously. Its administration reduces the haeme deficit, hence limits the production of porphyrins precursors by the body. Availability of hemin in Pakistan is not promising while alternatives such as intravenous infusion of glucose, and pain relievers like Nalbuphine, a man-made opioid analgesic, and Morphine are short-term treatments. Haeme Arginate (HA), a compound of haeme and arginine, is equivalent to hematin in the treatment of AIP. Long-term weekly intravenous infusions of prophylactic HA prevent severity and frequency of porphyric attacks in patients with AIP.4 While haeme therapy is recommended if a patient exhibits neurological impairment, liver transplant appears to be the last resort in patients with recurrent clinical manifestations. To effectively mediate the growing need of Hemin in Pakistan, a systematic plan with effective and immediate steps must be introduced. The regulatory authorities must expedite the approval and licensing process of appropriate medication that would meet the growing need of the country, while not compromising on its quality. The possibility of local production should be explored, while strengthening international ties aimed at importing affordable medication. The government should focus on initiating partnerships with international organizations, non-governmental organizations (NGOs) and global health initiatives. Nationwide workshops and informative campaigns towards healthcare work should be a priority, to raise awareness of the situation and the proper steps that should be taken to minimize its adverse effects. Empowering patient advocacy groups would be beneficial in recognizing any shortcomings of the plan and to divert resources accordingly.

Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates

ObjectiveAcute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks...

Main metabolic pathways of Solanum nigrum L. hyperaccumulating cadmium except of copper simultaneously through differentially expressed proteins analysis

Determining the hyperaccumulation mechanism of Solanum nigrum L., which exclusively accumulates cadmium (Cd), presents significant challenges due to the difficulty in identifying its unique characteristics. While some metabolic pathways related to Cd accumulation can be explored, there are no methods to ascertain if other heavy metals may share the same pathways. Isobaric tags for relative and absolute quantitation (iTRAQ) were employed to investigate the metabolic pathways associated with Cd hyperaccumulation and Cu accumulation (non-Cu hyperaccumulator) by comparing differentially expressed proteins (DEPs). The results showed that 27 intersecting DEPs reflecting relative metabolic pathways related to Cd accumulation were identified by comparing DEPs in leaves and roots, including carbon metabolism, aminoacyl-tRNA biosynthesis, phagosome, peroxisome, as well as starch and sucrose metabolism. These pathways might be responsible for the values of Cd enrichment factor (EF) and translocation factor (TF) exceeding 1, associated with key proteins participated in phosphoenolpyruvate, carboxylase, chloroplastic catalytic activity, and granule-bound starch synthase I. The combined metabolic pathways identified by 2 intersecting DEPs related to Cu accumulation could result in Cu EF >1 in the 0.2 Cu mg kg−1 treatment, EF <1 in the 5 mg kg−1 treatment, and TF<1 in both treatments, associated with key proteins, which might concern photosynthesis-antenna proteins and hydroxymethylbilane synthase. No metabolic pathways related to simultaneous accumulation of Cd and Cu has been identified. The identified DEPs were validated using Western blotting with five key proteins. Additionally, Western blotting and yeast mutant confirmed the presence of proteins related to carbon fixation in photosynthetic organisms, carbon metabolism, peroxisome, as well as starch and sucrose metabolism. Photosynthetic, O2•−, H2O2 and non-enzymatic antioxidants indices reflecting protein-related differences indirectly supported the above results. These findings are crucial for further exploration of the Cd hyperaccumulation mechanism.

Acute intermittent porphyria: a disease with low penetrance and high heterogeneity.

Acute intermittent porphyria (AIP) is caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS), a key enzyme in the heme biosynthesis pathway. AIP is an autosomal dominant disorder characterized by low penetrance and a highly heterogenous clinical presentation. The estimated prevalence of AIP is 5-10 cases per 100,000 persons, with acute attacks manifesting in less than 1% of the at-risk population. This low frequency of attacks suggests significant roles for oligogenic inheritance and environmental factors in the pathogenesis of the disease. In recent years, identification of several modifier genes has advanced our understanding of the factors influencing AIP penetrance and disease severity. This review summarizes these factors including the impact of specific HMBS mutations, oligogenic inheritance, mitochondrial DNA copy number, age, sex, the influence of sex hormones, and the role of environmental factors. Further studies into the etiology of AIP disease penetrance should inform pathogenesis, potentially allowing for the development of more precise diagnostic and therapeutic approaches.

Assessing predictions on fitness effects of missense variants in HMBS in CAGI6.

This paper presents an evaluation of predictions submitted for the "HMBS" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the median correlation (≥ 0.34) observed among these predictors, especially the top predictions from different groups, was greater than the correlation observed between their predictions and the actual experimental results. Most predictors were moderately successful in distinguishing between deleterious and benign variants, as evidenced by an area under the receiver operating characteristic (ROC) curve (AUC) of approximately 0.7 respectively. Compared with the recent two rounds of CAGI competitions, we noticed more predictors outperformed the baseline predictor, which is solely based on the amino acid frequencies. Nevertheless, the overall accuracy of predictions is still far short of positive control, which is derived from experimental scores, indicating the necessity for considerable improvements in the field. The most inaccurately predicted variants in this round were associated with the insertion loop, which is absent in many orthologs, suggesting the predictors still heavily rely on the information from multiple sequence alignment.

Acute intermittent porphyria: A case report with an unlisted HMBS gene variant (c.345–2A>C)

We report a case of acute intermittent porphyria in a 19-year-old patient, linked to an unlisted variant of the gene encoding hydroxymethylbilane synthase c.345–2A>C. Given the very low prevalence of porphyria in the general population, diagnosis is rarely made initially and may mainly mimic Guillain-Barré syndrome. Considering this, we provide an overview addressing various ways the disease manifests, paraclinical investigations, pathophysiology, and available therapeutic options. Specifically, human heme therapy in the case of acute crises is nearly unanimous in the literature. However, there is no consensus on the management between crises if the current first line choice treatment, namely givosiran, is not accessible. We report the clinical follow-up proposed for this patient.

Episodic Hyponatremia in Acute Intermittent Porphyria: A Case Report

Background: Acute intermittent porphyria (AIP) is an uncommon, ubiquitously distributed autosomal dominant disorder with low penetrance characterized by decreased enzyme activity of hydroxymethylbilane synthase (HMBS) an enzyme of heme synthesis pathway. It is often an elusive diagnosis due to rarity and non-specific signs and symptoms. Case report: A 28 years old female from Nawalparasi (district in central Nepal) presented with history of recurrent episodes of abdominal pain and vomiting. Her current episode began two weeks before presentation to our center. Abdominal pain was diffuse, colicky in nature without exacerbating or relieving factor. There was no postural or diurnal variation. On examination, there was no tenderness and abdominal examination findings were unremarkable. Her biochemical investigations were unremarkable except for severe hyponatremia (S. Na of 100mmol/L) which was SIADH/SIADH like presentation (Table 1 and Table 2). Severe episodic hyponatremia, port-wine color of urine, gastrointestinal symptoms and previous hospital stay two years back with similar episode of hyponatremia and abdominal pain were valuable clues for suspicion of acute porphyria. On further evaluation, patient was found to have presence of porphyrogenic precursors in urine and diagnosis of acute intermittent porphyria was confirmed. After diagnosis, she was managed conservatively with carbohydrate loading with intravenous dextrose, opioids and pregabalin as analgesics. Her symptoms gradually improved, hyponatremia subsided and was discharged in normal condition. Conclusion: Acute intermittent porphyria has signs and symptoms common to several clinical, neurological, psychiatric and gastroenterological pathologies, which complicate diagnosis. In young patients with hyponatremia (with SIADH –like picture), AIP should be considered in differential diagnosis.

FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction

Systematically predicting the effects of mutations on protein fitness is essential for the understanding of genetic diseases. Indeed, predictions complement experimental efforts in analyzing how variants lead to dysfunctional proteins that in turn can cause diseases. Here we present our new fitness predictor, FiTMuSiC, which leverages structural, evolutionary and coevolutionary information. We show that FiTMuSiC predicts fitness with high accuracy despite the simplicity of its underlying model: it was among the top predictors on the hydroxymethylbilane synthase (HMBS) target of the sixth round of the Critical Assessment of Genome Interpretation challenge (CAGI6) and performs as well as much more complex deep learning models such as AlphaMissense. To further demonstrate FiTMuSiC’s robustness, we compared its predictions with in vitro activity data on HMBS, variant fitness data on human glucokinase (GCK), and variant deleteriousness data on HMBS and GCK. These analyses further confirm FiTMuSiC’s qualities and accuracy, which compare favorably with those of other predictors. Additionally, FiTMuSiC returns two scores that separately describe the functional and structural effects of the variant, thus providing mechanistic insight into why the variant leads to fitness loss or gain. We also provide an easy-to-use webserver at https://babylone.ulb.ac.be/FiTMuSiC, which is freely available for academic use and does not require any bioinformatics expertise, which simplifies the accessibility of our tool for the entire scientific community.

A rare cause for seizures in an adult male – First report of a rare mutation in HMBS gene (c.730_731del) from India

A rare cause for seizures in an adult male – First report of a rare mutation in HMBS gene (c.730_731del) from India

Hydroxymethylbilane Synthase Gene Mutation: The Hidden Driver of Abdominal Pain and Neurological Symptoms in Acute Intermittent Porphyria

Abstract: Mutations in the hydroxymethylbilane synthase (HMBS) gene can lead to a deficiency of the HMBS enzyme, allowing porphyrins to accumulate to toxic levels in the liver and other organs, leading to acute intermittent porphyria (AIP). This case report describes the medical journey of a 20-year-old female, previously in good health, who experienced multiple hospitalizations and clinic visits due to severe abdominal pain episodes and remained undiagnosed for over 6 years. Despite the nonspecific nature of these symptoms, a suspicion of acute porphyria confirmed by genetic analysis revealed a splice pathogenic variant (c.826-2A&gt;T) in the HMBS gene in a heterozygous state. As the disease progressed, the patient developed a series of complications, including hyponatremia, autonomic instability, and motor neuropathy, culminating in complete paralysis (quadriplegia) and respiratory failure. The case highlights the importance of early recognition and differential diagnoses in managing AIP, with genetic testing playing a crucial role in confirming the diagnosis.

Reduced ribonucleotide reductase RRM2 subunit expression increases DNA damage and mitochondria dysfunction in woody breast chickens.

The aim of this study was to investigate the roles of ribonucleotide reductase subunit M2 (RRM2; subunit of ribonucleotide reductase) in severe woody breast (WB) and normal breast muscles. 40 8-week-old male Ross-708 broiler chickens. Quantitative PCR was performed to determine gene expression, and commercial ELISA/assay kits were used to obtain several enzymatic activities. Results showed that RRM2 activity (P = .0002) and RRM2 (P = .05) and hydroxymethylbilane synthase expression (impaired oxygen transport and metabolism, P = .002) were reduced in WB, while caveolin-3 (defected membrane integrity, P = .09), endoglin (increased fibrosis, P = .06), and secreted protein acidic rich in cysteine (metabolic dysregulation, P = .09) expression tended to increase in WB. WB tended to have increased levels of homocysteine (P = .06), aspartate aminotransferase mitochondria (P = .02), pyruvate kinase (P = .04), DNA damage (P = .06), creatine kinase (P = .05), and triglyceride (P = .002) but decreased ATPase activity (P = .01), all indicating mitochondria dysfunction and tissue damage. In this study, differences in various enzyme activities and increased DNA damage suggest that RRM2-mediated mitochondrial abnormalities may play a role in WB myopathy.

Causal effect of porphyria biomarkers on alcohol-related hepatocellular carcinoma through Mendelian Randomization.

According to some cohort studies, an association exists between acute intermittent porphyria (AIP) and liver cancer. However, establishing a definitive causal relationship between porphyria and hepatocellular carcinoma (HCC) remains challenging. Prexisting studies regarding porphyria biomarkers and alcohol-related hepatocellular carcinoma (AR-HCC) make possible an entry point. In this study, we aimed to investigate the causal relationships between biomarkers of two types of porphyria, AIP and congenital erythropoietic porphyria (CEP), and AR-HCC. Single-nucleotide polymorphisms (SNPs) associated with porphobilinogen deaminase (PBGD) and uroporphyrinogen-III synthase (UROS), along with outcome data on AR-HCC, were extracted from public genome-wide association studies (GWAS). The GWAS data were then used to explore the potential causal relationships via a two-sample Mendelian randomization (MR) analysis. The effect estimates were calculated using the random-effect inverse-variance-weighted (IVW) method. Additionally, the Cochrane's Q test, MR-Egger test, and leave-one-out analysis were conducted to detect heterogeneity and pleiotropy in the MR results. Using the IVW method as the primary causal effects model in the MR analyses, we found that both PBGD (effect estimate = 1.51; 95% CI, from 1.08 to 2.11, p = 0.016) and UROS (effect estimate = 1.53; 95% CI, from 1.08 to 2.18, p = 0.018) have a significant causal effect on AR-HCC. Our findings revealed a causal effect of both PBGD and UROS on AR-HCC, suggesting that both AIP and CEP have a causal association with AR-HCC.

Whole-genome resequencing identifies candidate genes and SNPs in genomic regions associated with shell color selection in the Pacific oyster, Crassostrea gigas

The various shell colors of bivalves not only result in a better visual perception but also show great commercial value as a highly potential breeding trait. Four shell color strains of Pacific oyster (Crassostrea gigas) characterized by black (SB), white (SW), gold (SG), and orange (SO) were bred purposefully for more than ten generations. In this study, whole-genome resequencing was performed on 20 oysters from each of the four strains, and a total of 14.67 million single nucleotide polymorphisms (SNPs) were obtained after stringent filtering, with an average sequencing depth of >10×. The population structure analysis provided support for the subdivision of all samples into four major genetic clusters corresponding to shell color phenotypes, indicating a high level of genomic differentiation driven by artificial selection. Then, a composite measure of fixation index (FST) and cross-population composite likelihood ratio (XP-CLR) allowed us to identify 336 to 414 candidate divergent regions (CDRs) in pairwise comparisons of different shell colors, with a total of 480 to 614 corresponding genes distributed. Of particular interest were tyrosinase (TYR) and perilipin2 (PLIN2) occurring with extremely high frequency, which participates in shell color determination by regulating melanin production and carotenoid metabolism, respectively. In addition, two genes, namely porphobilinogen deaminase (PBGD) and hephaestin (HEPH), may have a potential function in the accumulation of specific porphyrin in orange shells, while the kynurenine 3-monooxygenase (KMO) gene, known to be involved in ommochrome biosynthesis, may contribute to the darker coloration in black shells. Further, a total of 304 SNPs were extracted from the exons of candidate genes mentioned above, of which 25 loci had highly significant differences among populations (p-value ≤0.01). After Sanger sequencing in another population, 14 SNPs were successfully validated as specific loci closely linked to different shell colors of black, white, gold, and orange, respectively. All in all, the results of this study shed light on the molecular basis of pigmentation and facilitate the selective breeding of C. gigas with desired phenotypic color.

Xenobiotics Triggering Acute Intermittent Porphyria and Their Effect on Mouse Brain Respiratory Complexes.

Heme enzyme dysfunction causes a group of diseases called porphyrias. Particularly, a decrease in porphobilinogen deaminase, involved in the third step of heme biosynthesis, leads to acute intermittent porphyria (AIP). Considering our previous works demonstrating the multiplicity of brain metabolisms affected by porphyrinogenic agents, this study aimed to elucidate whether they cause any alteration on the mitochondrial respiratory chain. The activities of respiratory chain complexes (I to IV) were measured in encephalon mitochondria of CF1 male mice receiving volatile anesthetics: isoflurane (2 mL/kg) and sevoflurane (1.5 mL/kg), ethanol (30%), allylisopropylacetamide (AIA) (350 mg/kg), and barbital (167 mg/kg). Moreover, they were compared versus animals with pathological levels of 5-aminolevulinic acid (ALA, 40 mg/kg). Complex I-III activity was induced by isoflurane and decreased by AIA, ethanol, and ALA. Complex II-III activity was increased by sevoflurane and decreased by isoflurane and AIA. Complex II activity was increased by sevoflurane and barbital and decreased by AIA, ethanol, and ALA. Complex IV activity was increased by barbital and ALA and decreased by sevoflurane. The damage to the respiratory chain by ALA could be reflecting the pathophysiological condition of patients with AIP. Better understanding the broad effect of porphyrinogenic drugs and the mechanisms acting on the onset of AIP is vital in translational medicine.

Acute Intermittent Porphyria: Flaccid Quadriplegia and Encephalopathy due to Posterior Reversible Encephalopathy Syndrome (PRES)

A deficiency of the enzyme HMB Hydroxymethylbilane synthase function, also known as porphobilinogen deaminase, leads to the emergence of acute intermittent porphyria (AIP). AIP is an uncommon form of hepatic porphyria inherited in an autosomal dominant fashion. We present a case involving a young girl who experienced a sudden onset of quadriparesis, a severe neurological condition that necessitated ventilator support due to respiratory distress. Her condition was consistent with motor axonal neuropathy, which is a characteristic feature of Acute Intermittent Porphyria (AIP). During her last hospital admission, she developed new-onset generalized tonic-clonic seizures, and MRI findings at that time indicated the presence of hyperintense lesions in the posterior parietal region, likely attributed to Posterior Reversible Encephalopathy Syndrome (PRES). To manage her symptoms, she received Dextrose saline due to the elevated levels of urinary porphobilinogen. This case underscores the significance of recognizing two alarming complications associated with porphyria, namely PRES and acute motor axonal neuropathy. Despite an appropriate and timely diagnosis, our efforts were unsuccessful in averting these complications. The unavailability of Hematin, a vital treatment for acute porphyria attacks, was the primary reason for her unfortunate demise.

Porphyria in an Adolescent Girl: A Clinician’s Quagmire

Abstract Background: Porphyrias are a group of potentially life-threatening, metabolic disorders resulting from defective heme biosynthesis. They have a myriad of multisystem manifestations and pose a diagnostic and management challenge. Acute intermittent porphyria (AIP) is a severe and the most common form of porphyria. Awareness of this uncommon entity and a high index of suspicion are warranted for a successful outcome. Clinical Description: A 12-year-old girl was referred to us with a history of severe pain in the abdomen and generalized tonic-clonic seizures. She had episodic abdominal pain for the past 6 months associated with abnormal menstrual cycles. She had acutely raised blood pressure. She had urine was orange-pink in color, which led us to suspect a diagnosis of AIP. A urine examination confirmed the presence of porphobilinogen. On genetic testing, a pathogenic missense variation (c.518G&gt;A) in exon 9 of the hydroxymethylbilane synthase (+) gene, which is autosomal dominant, was detected, which confirmed the diagnosis. Management: Seizures were treated with lorazepam and levetiracetam. Hypertension was managed with labetalol infusion followed by amlodipine. Tramadol was given for severe pain abdomen. Persistent severe hyponatremia (serum sodium 104 mEq/L) was initially managed with normal saline 3% saline and later, with fluids restriction. Conclusion: The diagnosis of AIP should be suspected, especially in pubertal girls who present more than once with persistent symptoms of acute abdomen, vomiting, hypertension, or symptoms linked to the menstrual cycle.

Functional and structural analysis of a novel splice site HMBS variant in a Chinese AIP patient.

Background: Acute intermittent porphyria (AIP) is a rare metabolic disorder that results from mutations in the gene encoding hydroxymethylbilane synthase (HMBS), an enzyme involved in heme biosynthesis. AIP follows an autosomal dominant inheritance pattern, but most carriers are asymptomatic. The clinical manifestations of AIP include acute attacks of abdominal pain and neuropsychiatric disturbances. The pathogenicity of novel HMBS variants identified in Chinese patients has not been well established. Objective: The article aims to identify the pathogenic mutation in an AIP patient and prove its pathogenicity through in vitro experiments. Methods: A 22-year-old female diagnosed with AIP participated in the study. Variant screening of her HMBS gene was carried out through Sanger sequencing. To ascertain the consequences of the newly discovered variant, we conducted in vitro experimentation targeting HMBS gene expression and enzymatic function. Additionally, protein structure analysis was performed. Cycloheximide treatment and UPF1-specific siRNA knockdown were employed to assess the impact of the mutation on the mechanism of non-sense-mediated mRNA decay (NMD). Results: A novel splice site variant in the HMBS gene (c.648_651+1delCCAGG) was detected in the patient, which caused aberrant mRNA splicing. In vitro experiments demonstrated that this variant significantly decreased the expression of HMBS. Further investigation confirmed that this decrease was due to NMD. Additionally, structural analysis indicated that this variant would destabilize the HMBS protein and impair its catalytic activity. To gain a comprehensive understanding of HMBS mutations in the context of AIP, we conducted a literature search on PubMed using the keywords 'HMBS' and 'Acute intermittent porphyria' from 2013 to 2023. This search yielded 19 clinical case reports written in English, which collectively described 220 HMBS gene mutations worldwide. Conclusion: The study identified and proved the pathogenicity of a novel splice site HMBS variant for the first time. Our results elucidated the pathological mechanism by which this mutation causes AIP through reducing HMBS expression and activity. These findings provide theoretical guidance for the diagnosis, treatment and genetic counseling of AIP patients.

Acute intermittent porphyria (AIP) in 27 year old female patient- Case report

Acute Intermittent Porphyria (AIP) is the most common acute and probably the most common inherited porphyria. AIP is caused due to deficiency of hydroxymethylbilane synthase (HMBS). AIP is characterized by a classical triad of abdominal pain, central nervous system abnormalities and peripheral neuropathy. We report a case of 27 year old female patient with recurrent episodes of acute abdominal pain. Patient underwent all laboratory &amp; imaging investigations at our centre.

Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a Bioinformatics Study

Imatinib (IMA) and nilotinib are the first and second generations of BCR-ABL tyrosine kinase inhibitors, which widely applied in chronic myeloid leukemia (CML) treatment. Here we aimed to provide new targets for CML treatment by transcriptome analysis. Microarray data GSE19567 was downloaded and analyzed from Gene Expression Omnibus (GEO) to identify common genes, which are downregulated or upregulated in K562-imatinib and K562-nilotinib treated cells. The differentially expressed genes (DEGs) were assessed, and STRING and Cytoscape were used to create the protein–protein interaction (PPI) network. In imatinib and nilotinib treated groups’ comparison, there were common 626 upregulated and 268 downregulated genes, which were differentially expressed. The GO analysis represented the enrichment of DEGs in iron ion binding, protein tyrosine kinase activity, transcription factor activity, ATP binding, sequence-specific DNA binding, cytokine activity, the mitochondrion, sequence-specific DNA binding, plasma membrane and cell-cell adherens junction. KEGG pathway analysis revealed that downregulated DEGs were associated with pathways including microRNAs in cancer and PI3K-Akt signaling pathway. Furthermore, upregulated DEGs were involved in hematopoietic cell lineage, lysosome and chemical carcinogenesis. Among the upregulated genes, MYH9, MYH14, MYL10, MYL7, MYL5, RXRA, CYP1A1, FECH, AKR1C3, ALAD, CAT, CITED2, CPT1A, CYP3A5, CYP3A7, FABP1, HBD, HMBS and PPOX genes were found as hub genes. Moreover, 20 downregulated genes, YARS, AARS, SARS, GARS, CARS, IARS, RRP79, CEBPB, RRP12, UTP14A, PNO1, CCND1, DDX10, MYC, WDR43, CEBPG, DDIT3, VEGFA, PIM1 and TRIB3 were identified as hub genes. These genes have the potential to become target genes for diagnosis and therapy of CML patients.