Human Mutation最新文献

Bloom syndrome (BS) is a rare genetic disorder associated with an elevated risk of cancer. In a national multicentre study, nine paediatric patients with BS and cancer were analysed. Median age at cancer diagnosis was 12 years. Four of the nine patients were diagnosed with BS prior to cancer detection. Six presented with solid tumours, whilst three had haematological malignancies. Six received polychemotherapy, often with dose reductions. Complications included prolonged aplasia, sepsis and early treatment discontinuation. Two patients received radiotherapy. Four relapsed, and four died, including one toxic death. However, five achieved remission, highlighting the possibility of curative treatment despite significant toxicities.

SLC35A1-CDG is a very rare type of congenital disorders of glycosylation (CDG) with only five cases known to date. Here, we review the literature and present new data from a sixth patient carrying the uncharacterized variant c.133A>G; p.Thr45Ala in the SLC35A1 gene. In addition to known clinical symptoms of SLC35A1-CDG, the patient presents with failure to thrive, short stature, café-au-lait spot, and preauricular ear tag. Even though examination of CDG markers transferrin (Tf), alpha-1-antitrypsin (A1AT), and apolipoprotein CIII (ApoCIII) revealed no abnormalities in serum, the patient’s fibroblasts showed significant alterations of protein expression or glycosylation of ICAM1, GP130, and TGN46 as well as differences in staining signals of lectins MAL-I, RCAI, and SNA and deviations in LC-MS analysis of total cellular N-glycans. Transfection of CRISPR/Cas9 generated SLC35A1 HEK293 knockout cells with either wild-type SLC35A1 or the c.133A>G variant restored the cellular CMP-Neu5Ac to wild-type levels, making a direct effect of p.Thr45Ala on the function of the transporter unlikely. Instead, our results imply that the residual transporter activity of 65% is caused by a decreased stability of the mutated SLC35A1 protein. Since O-GlcNAcylation was affected as well, energy and lipid homeostasis were analyzed and found to be significantly altered. Notably, proliferation and glycosylation of the SLC35A1-deficient patient fibroblasts were enhanced by supplementation of the cell culture medium with 10 mM GlcNAc.

Cardiac arrest (CA) prevention continues to be a substantial hurdle for global public health. Although dyslipidemia and 25-hydroxyvitamin D (25(OH)D) insufficiency are recognized contributing factors for cardiovascular disease (CVD), their causal relationship with CA risk is still uncertain. Here, we explored these correlations and pinpointed possible therapeutic targets for CA prevention though Mendelian randomization (MR). Both two-sample and multivariable MR analysis methods were conducted to assess how serum lipid traits and 25(OH)D influence the susceptibility to develop CA. Nine thousand nine hundred eighty-eight participants in total from the National Health and Nutrition Examination Survey (NHANES) engaged in validating the relationship between the concentrations of 25(OH)D and cardiovascular mortality in individuals with dyslipidemia. The integration of MR with expression quantitative trait locus (eQTL) analysis enabled the identification of druggable targets, and molecular docking was used to screen small molecules, which were subsequently validated in animal models. The MR results revealed that both elevated levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), as well as triglycerides (TGs), significantly contributed to an increased CA risk (p < 0.05). Conversely, higher amounts of apolipoprotein A1 (ApoA1), high-density lipoprotein cholesterol (HDL-C), and 25(OH)D were causally contributing to a decreased risk of CA (p < 0.05). A bidirectional causal relationship was observed among LDL-C, TG, ApoB, and 25(OH)D levels. Mediation MR suggests that dyslipidemia and low 25(OH)D status could potentially elevate the CA risk through pathways involving myocardial infarction, diabetes, and hypertension. NHANES data confirmed that higher 25(OH)D were tied to decreased risks of all-cause and CVD death among those with dyslipidemia (p < 0.01). Notably, chromobox 6 (CBX6), negatively associated with CA risk (OR = 0.87, 95% CI: 0.78–0.99, p = 0.029), was determined to be a target of both sanguinarine and lycorine, which improved lipid profiles and 25(OH)D in mice. In conclusion, dyslipidemia and low 25(OH)D status are causally related to CA risk, they appear to interact, and their coexistence may confer a higher risk of CVD mortality. Compounds targeting specific genes can both improve dyslipidemia and elevate 25(OH)D levels, thereby exhibiting potential therapeutic effects for preventing CA. Overall, this study enhances our understanding of the underlying mechanisms linking dyslipidemia, 25(OH)D deficiency, and CA and offers new perspectives for prevention.

Background: Some 234 mutations in the small SOD1 gene have been reported to cause amyotrophic lateral sclerosis. However, the pathogenic mechanisms, particularly of those mutations affecting polypeptide length, are contested. It is presently unknown whether all reported nonsense mutations in SOD1 are causative for ALS. The emergence of promising new anti-SOD1 drugs has made it imperative to gain further insight into clinical–genetic aspects of ALS for deciding which patients to treat in clinical practice and include in drug trials.

Objective: This study is aimed at comprehensively analyzing the clinical phenotypes associated with ALS-causing SOD1 mutations that alter the polypeptide length. The specific focus is on the age at which symptoms manifest and the survival duration.

Methods: Data were collected from web databases, published reports, conference presentations, and personal communications up to November 2023. The clinical endpoints, including age at symptom onset and age at death, were subjected to survival analysis. Comparative analyses were performed between frameshift and nonframeshift variants.

Results: A cohort of 146 ALS patients harboring 38 different nonmissense SOD1 variants was analyzed. The mean age of disease onset was 46.9 years, with a mean survival duration of 49 months. Significant heterogeneity was observed in clinical outcomes, with earlier disease onset and reduced survival associated with specific mutations. Notably, frameshift mutations proximal to the N-terminus showed a higher risk of early ALS onset compared to more distal mutations.

Conclusions: The clinical phenotypes of ALS patients with nonmissense SOD1 mutations are highly variable and dependent on the specific mutation. These findings underscore the necessity of including diverse SOD1 mutation carriers in therapeutic trials and suggest that both loss-of-function and gain-of-function mechanisms may contribute to ALS pathology.

Epistatic interaction detection plays a pivotal role in understanding the genetic mechanisms underlying complex diseases. The effectiveness of epistatic interaction detection methods primarily depends on their interaction quantification measures and search strategies. In this study, a two-stage ant colony optimization algorithm based on composite multiscale part mutual information (ACOCMPMI) is proposed for detecting epistatic interactions. In the first stage, composite multiscale part mutual information is developed to quantify epistatic interactions, and an improved ant colony optimization algorithm incorporating filter and memory strategies is employed to search for potential epistatic interactions. In the second stage, an exhaustive search strategy and a Bayesian network score are adopted to further identify epistatic interactions within the candidate SNP set obtained in the first stage. ACOCMPMI is compared with five state-of-the-art methods, including epiACO, FDHE-IW, AntEpiSeeker, SIPSO, and MACOED, using simulation data generated from 11 epistatic interaction models. Furthermore, ACOCMPMI is applied to detect epistatic interactions in a real dataset of age-related macular degeneration. The experimental results show that ACOCMPMI is a promising method for epistatic interaction detection.

Introduction: Biallelic pathogenic variants in LARP7 result in Alazami syndrome, which is characterized by global developmental delay, cognitive dysfunction, and dysmorphic features. Cardiac and skeletal phenotypes are reported in about 30% of individuals. We report three new individuals with Alazami syndrome and functional characterization of LARP7 variants in this study.

Materials and Methods: We reviewed electronic patient charts. We applied the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification algorithms. We performed a 3D protein modeling tool for in silico prediction and functional characterization of LARP7 variants using qPCR gene expression experiments. We reviewed the medical literature for Alazami syndrome and LARP7.

Results: We report three individuals from two unrelated families with characteristic phenotypes suggestive of Alazami syndrome. We identified a homozygous novel missense LARP7 likely pathogenic variant (p.Asp54Val) in Family 1 and a homozygous novel pathogenic LARP7 variant (p.Lys219Glu∗) in Family 2 using clinical exome sequencing. 3D protein modeling showed large structural changes for both variants compared to wildtype. The functional characterization showed a statistically significant difference in LARP7 expression between affected individuals and wildtype control. We report phenotypic variability within the same family that the cardiac phenotype was only present in Family 1, Case 2. There were < 60 individuals with Alazami syndrome reported to date.

Conclusion: We report three new individuals with Alazami syndrome and two novel variants in LARP7. We report the first missense LARP7 variant associated with Alazami syndrome. We report the protein 3D structure of LARP7 variants. We show a relationship between the p.Asp54Val LARP7 variant and LARP7 expression levels. We think that this could be due to abnormal RNA binding of LARP7 as per the 3D protein modeling prediction tool.

Background: The apoptosis affected the prostate adenocarcinoma (PRAD); we aimed to explore the potential pathogenesis of high-risk patients based on the apoptosis features.

Method: The RNA-seq data of patients and apoptosis genes were used for apoptosis score calculation via “GSVA” package; then, the weighted gene coexpression network analysis (WGCNA) and Lasso algorithm were performed for a RiskScore model. After that, the “maftools” package was applied for the somatic mutation analysis. By combining the Kaplan–Meier (KM) survival curves in order to compare the prognosis of different subgroups of patients, Cell Counting Kit-8 (CCK-8), EdU staining, and Transwell assays were performed. Protein expression was measured using western blotting. Finally, the activity of PRAD cells in macrophage polarization was detected using coculture and immunofluorescence assays.

Results: The PRAD samples had significantly lower apoptosis scores, and the RiskScore supported the risk stratification of patients. In somatic mutation analysis, EPHB1 and KIF13A from the top six mutant genes were overexpressed in 22RV1 and PC-3 tumor cells, and low levels of EPHB1 indicated a better prognosis. Overexpression or knockdown of EPHB1 affected cell viability, proliferation, and invasion. We found that high expression of EPHB1 interacting with GSK3B protein promoted the expression of p-SMAD3 in 22RV1 cells with high levels of antiapoptotic and invasion markers (BCL2, Snail, and N-CAD). Importantly, GSK3B and EPHB1 knockdown inhibited p-SMAD3 activation and promoted proapoptotic features, accompanied by a reduction in macrophage M2 polarization.

Conclusion: This study revealed that EPHB1 plays a pivotal role in activating the EPHB1-GSK3B-SMAD3 pathway to facilitate PRAD progression.

Objective: Combination of CT imaging and RNA sequencing techniques was used to explore the potential biomarkers specific to lung adenocarcinoma within pulmonary ground-glass nodules.

Method: The imaging and pathological data of patients with pulmonary ground-glass nodules who underwent chest CT scanning were confirmed through surgical procedures. Based on the pathological results, the patients were categorized into a benign nodule group and a malignant nodule group. Subsequently, RNA sequencing was conducted to analyze gene expression information in the pulmonary ground-glass nodules of these 16 patients.

Results: CT signs demonstrated statistical significance in both benign and malignant nodules. A total of 2080 upregulated genes and 1240 downregulated genes were identified through RNA sequencing in malignant nodules compared to benign nodules. CST1 exhibited increased expression among the upregulated genes in lung adenocarcinoma tissues compared to lung tissues. Among the downregulated genes, only GIMAP1-GIMAP5 showed decreased expression in lung adenocarcinoma tissues. Finally, we validated the clinical significance of CST1 and GIMAP1-GIMAP5 in patients with lung adenocarcinoma, particularly highlighting a strong correlation between GIMAP1-GIMAP5 expression levels and prognosis for patients. A visual nomogram predictive model for pulmonary ground-glass nodules was constructed (area under the receiver operating characteristic curve (AUC) > 0.8).

Conclusion: We constructed a nomogram combining CST1 and GIMAP1-GIMAP5 expression for predicting lung adenocarcinoma in ground-glass nodules in the context of COVID-19. This nomogram addresses the unique diagnostic challenges posed by COVID-19, where overlapping pulmonary imaging findings between viral pneumonia and early lung cancer necessitate robust molecular-aided discrimination.

Dilated cardiomyopathy (DCM) is a serious public health problem that increases the risk of developing heart failure. Most recently, increasing evidence has shown that mitochondrial dysfunction caused by mitochondrial tRNA (mt-tRNA) mutations plays a putative role in the pathogenesis of this disease, despite its pathophysiology remaining poorly understood. In this study, a novel 12265A>G mutation in mt-tRNA^Ser(AGY) was identified from a Chinese pedigree with maternally inherited DCM, together with a known mt-tRNA^Cys 5821G>A mutation. Interestingly, the novel m.12265A>G mutation changed the well-conserved adenosine at Position 73 (A73) to guanine (G73) at the 3 ^′-end of the mt-tRNA^Ser(AGY) acceptor arm, while the G-to-A transition at 5821 occurred at the acceptor arm of mt-tRNA^Cys, disrupting conserved base pairing (G6-C67). Transmitochondrial cybrid-based study demonstrated that cell lines with m.12265A>G and m.5821G>A mutations showed impaired mitochondrial functions, including significant reductions in mitochondrial ATP, membrane potential, NAD⁺/NADH ratio, mitochondrial DNA (mtDNA) content, mitochondrial transcription factor A (TFAM) mRNA expression levels, and respiratory chain enzyme Complex I and III activities, whereas the levels of reactive oxygen species (ROS), calcium ions (Ca²⁺), and lactate were enhanced in mutant cells compared to controls (p < 0.05). Thus, the m.12265A>G and m.5821G>A mutations may affect mt-tRNA metabolism and impair mitochondrial function, which is involved in DCM. Taken together, our study broadens the genotypic interpretation of mt-tRNA mutations linked to disease.

Rett syndrome (RTT) is a rare, X-linked, severe neurodevelopmental disorder, predominantly associated with pathogenic variants in the methyl-CpG-binding protein-2 (MECP2) gene, with an increasing number of atypical RTT or RTT-like individuals having pathogenic variants in other genes, such as cyclin-dependent kinase-like 5 (CDKL5) or forkhead box G1 (FOXG1). However, ~20% of individuals with a clinical diagnosis of RTT remain genetically undiagnosed, highlighting the importance of ongoing genomic and functional studies to expand the genetic spectrum of RTT. We present a female who was born to healthy nonconsanguineous parents and presented with severe intellectual disability, macrocephaly, ataxia, absent speech, and poor eye contact. The affected individual was clinically diagnosed with atypical RTT, but genetic testing showed no pathogenic variants in MECP2, CDKL5, or FOXG1. Singleton whole genome sequencing was conducted, which identified a heterozygous stop–gain variant [NM_001170629.2: c.5017C>T, p.(Arg1673 ^∗)], in the chromodomain-helicase-DNA-binding protein 8 (CHD8) gene. Variant curation revealed its absence in unaffected populations, in silico predictions of pathogenicity, and an existing association with intellectual developmental disorder with autism and macrocephaly (IDDAM) (OMIM #615032). In vitro functional analyses, including Western blots, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and proteomic analyses, demonstrated a significant reduction of the CHD8 transcript and two CHD8 protein isoforms in the proband’s skin fibroblasts relative to control fibroblasts. Additionally, proteomic analysis indicated a significant reduction of the MeCP2 protein, indicating a possible molecular link between CHD8 and MeCP2 and thus clinically between IDDAM and RTT. As the affected individual’s phenotype is consistent with atypical RTT, our results suggest that CHD8 could be considered in the expanding genetic spectrum of atypical RTT, which may assist the diagnosis of other MECP2-negative RTT individuals.