Pathogenic Missense Mutations Research Articles

Delusions of love and passion in the behavioral variant of frontotemporal dementia

ABSTRACT sErotomania (de Clérambault’s syndrome) refers to the delusional belief that another person, usually socially unreachable, is in love with the holder of the delusion. The occurrence of erotomania in Frontotemporal Dementia has rarely been reported. We present the unique case of a 59-year-old woman with a strong family history of early-onset dementia in whom erotomania was the initial manifestation that led to a diagnosis of definite Behavioral Variant of Frontotemporal Dementia with a pathogenic missense mutation in the MAPT gene. Based on this case, we propose a hypothetical model for developing erotomania in patients with FTD.

Pathogenic mutations of human phosphorylation sites affect protein–protein interactions

Despite their lack of a defined 3D structure, intrinsically disordered regions (IDRs) of proteins play important biological roles. Many IDRs contain short linear motifs (SLiMs) that mediate protein-protein interactions (PPIs), which can be regulated by post-translational modifications like phosphorylation. 20% of pathogenic missense mutations are found in IDRs, and understanding how such mutations affect PPIs is essential for unraveling disease mechanisms. Here, we employ peptide-based interaction proteomics to investigate 36 disease-associated mutations affecting phosphorylation sites. Our results unveil significant differences in interactomes between phosphorylated and non-phosphorylated peptides, often due to disrupted phosphorylation-dependent SLiMs. We focused on a mutation of a serine phosphorylation site in the transcription factor GATAD1, which causes dilated cardiomyopathy. We find that this phosphorylation site mediates interaction with 14-3-3 family proteins. Follow-up experiments reveal the structural basis of this interaction and suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by masking a nuclear localisation signal. Our results demonstrate that pathogenic mutations of human phosphorylation sites can significantly impact protein-protein interactions, offering insights into potential molecular mechanisms underlying pathogenesis.

JAG1 Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis in 813 Congenital Hypothyroidism in China.

Congenital hypothyroidism (CH) is indeed a prevalent neonatal endocrine disorder, affecting approximately 1 in 2000-3000 newborns worldwide, and 1 in 2400 newborns in China. Despite its high incidence, the genetic causes of CH, particularly those related to thyroid dysgenesis (TD), are still not well understood. However, previous studies have suggested that JAG1 may be a potential susceptibility gene for congenital thyroid defects. To explore the association between JAG1 and CH, we screened JAG1 variants in a large cohort of 813 CH patients. We performed genetic analysis of JAG1 using next-generation sequencing in 813 CH cases. The pathogenicity of the variants was assessed by bioinformatics softwares, protein sequence conservation analysis, and hydrophobic analysis. Further genetic analysis was conducted targeting 20 CH-related genes in these 25 JAG1 variant carriers. We identified 10 pathogenic missense mutations (p.V45L, p.V272I, p.P552L, p.G610E, p.G852D, p.A891T, p.E1030K, p.R1060W, p.A1131T, p.P1174L) carried by 25 patients, the mutation rate of JAG1 in CH was 3.08%. Among these 25 patients, 16 with 1 variant, 6 with 2 variants, and the other 3 with 3 variants. Our findings indicated that JAG1 variants confer genetic susceptibility to both TD and DH, but with different inheritance models. JAG1 variants lead to TD mainly through monogenic model, while for DH cases, both monogenic mechanisms and oligogenic mechanisms play a pivotal role. Oligogenicity may contribute to the disease severity of DH. JAG1 is a shared genetic factor in TD and DH, with a detection rate of 3.08% in Chinese individuals with CH. A comparison between the oligogenic and monogenic groups suggests a gene dosage effect in CH. Patients with the same JAG1 mutation exhibit diverse clinical phenotypes, indicating complex mechanisms underlying phenotypic heterogeneity.

A Case Series of Three Patients with Cleidocranial Dysplasia: Clinical Presentation and Diagnostic Considerations.

Cleidocranial dysplasia (CCD) is a rare genetic condition that affects the bones and teeth. In our study, we presented three cases of CCD, including one with a new mutation and two with a family history. Case 1 had a unique heterozygous frameshift mutation (NM_001015051,c.762del, p.(Ser256Valfs*2)), while Case 2 and her brother (Case 3) had a common pathogenic missense mutation (NM_001015051,c.674G, p.Arg225Gln), which was also found in their father. The mutation in Case 1 was not reported before. Interestingly, the symptoms in Case 1, with the new mutation, were less severe than the other cases and the previous reports.

Protein destabilization underlies pathogenic missense mutations in ARID1B.

ARID1B is a SWI/SNF subunit frequently mutated in human Coffin-Siris syndrome (CSS) and it is necessary for proliferation of ARID1A mutant cancers. While most CSS ARID1B aberrations introduce frameshifts or stop codons, the functional consequence of missense mutations found in ARID1B is unclear. We here perform saturated mutagenesis screens on ARID1B and demonstrate that protein destabilization is the main mechanism associated with pathogenic missense mutations in patients with Coffin-Siris Syndrome.

Most Monogenic Disorders Are Caused by Mutations Altering Protein Folding Free Energy.

Revealing the molecular effect that pathogenic missense mutations have on the corresponding protein is crucial for developing therapeutic solutions. This is especially important for monogenic diseases since, for most of them, there is no treatment available, while typically, the treatment should be provided in the early development stages. This requires fast targeted drug development at a low cost. Here, we report an updated database of monogenic disorders (MOGEDO), which includes 768 proteins and the corresponding 2559 pathogenic and 1763 benign mutations, along with the functional classification of the corresponding proteins. Using the database and various computational tools that predict folding free energy change (ΔΔG), we demonstrate that, on average, 70% of pathogenic cases result in decreased protein stability. Such a large fraction indicates that one should aim at in silico screening for small molecules stabilizing the structure of the mutant protein. We emphasize that knowledge of ΔΔG is essential because one wants to develop stabilizers that compensate for ΔΔG, but do not make protein over-stable, since over-stable protein may be dysfunctional. We demonstrate that, by using ΔΔG and predicted solvent exposure of the mutation site, one can develop a predictive method that distinguishes pathogenic from benign mutations with a success rate even better than some of the leading pathogenicity predictors. Furthermore, hydrophobic-hydrophobic mutations have stronger correlations between folding free energy change and pathogenicity compared with others. Also, mutations involving Cys, Gly, Arg, Trp, and Tyr amino acids being replaced by any other amino acid are more likely to be pathogenic. To facilitate further detection of pathogenic mutations, the wild type of amino acids in the 768 proteins mentioned above was mutated to other 19 residues (14,847,817 mutations), the ΔΔG was calculated with SAAFEC-SEQ, and 5,506,051 mutations were predicted to be pathogenic.

DNA binding affinity of pathogenic missense mutations in the ARID domain of ARID1A

DNA binding affinity of pathogenic missense mutations in the ARID domain of ARID1A

Derivation of two human induced pluripotent stem cell lines carrying a missense mutation in FHL1 (c.377G > A, p.C126Y) linked to familial muscular dystrophy

FHL1 gene locates in the Xq26 region and encodes for four and half LIM domain protein 1. It plays a crucial role in muscle cells and mutations in FHL1 are related to muscular dystrophy (MD). Peripheral blood mononuclear cells (PBMCs) were obtained from 2 family patients with MD that carry a pathogenic missense mutation in FHL1 (c.377G > A, p.C126Y). Induced pluripotent stem cells (iPSCs) were generated by PBMCs reprogramming using the lentiviral-hSTEMCCA-loxP vector, obtaining FHL1-T and FHL1-V iPSCs lines from patients. FHL1 genotype was maintained, and stemness and pluripotency were confirmed in both iPSCs lines.

Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses.

NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents. Clinical phenotype, treatment, and prognosis were analyzed. Nine patients with NLRP3-AID were enrolled between December 2014 and October 2022 with an average follow-up period exceeding 30 months. The median age of onset was 12 months, and 66.7% were younger than 3 years old. The diagnosis was significantly delayed and the median delay duration was 115 months. The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). Two cases of chronic infantile neurological cutaneous articular syndrome (CINCA) had clubbed fingers, one with interstitial lung disease, a finding rarely reported. Treatment with glucocorticoids (77.8%) and biologic agents (33.3%) yielded 66% complete remission and 33% partial remission. Genetic analysis identified eight pathogenic NLRP3 missense mutations, including one novel mutation. Our study illuminated the distinct clinical and genetic features of Chinese NLRP3-AID patients, emphasizing the significance of early genetic screening. Despite delayed diagnosis, treatment primarily with glucocorticoids and biologic agents, led to favorable outcomes. Genetic heterogeneity, including a novel mutation, highlighted the complexity of NLRP3-AID in this population.

OmeDDG: Improved Protein Mutation Stability Prediction Based on Predicted 3D Structures.

Determining changes in the protein's thermal stability following mutations is critical in protein engineering and understanding pathogenic missense mutations. Despite the development of various computational methods to predict the effects of single-point mutations, their accuracy remains limited. In this study, we propose a new computational method, OmeDDG, that more accurately predicts mutation-induced Gibbs free energy changes in protein folding (ΔΔG). OmeDDG takes the sequences of wild-type and mutant proteins as input, utilizes OmegaFold to obtain the 3D structure, employs a convolutional neural network to extract structural features, and combines them with protein mutation features and pretraining features to predict the stability of single-point mutations in proteins. We performed a comprehensive comparison between OmeDDG and other available prediction methods on four blind test datasets, confirming that OmeDDG can effectively enhance protein mutation prediction performance. Notably, on the antisymmetric dataset Ssym, OmeDDG achieves the best performance, demonstrating favorable antisymmetry with PCC = 0.79 and RMSE = 0.96 for forward mutations and PCC = 0.77 and RMSE = 0.97 for reverse mutant types.

Engineered mischarged transfer RNAs for correcting pathogenic missense mutations

Missense mutations account for approximately 50% of pathogenic mutations in human genetic diseases, and most lack effective treatments. Gene therapies, gene editing, and RNA therapies, including transfer RNA (tRNA) modalities, are common strategies for genetic disease treatments. However, reported tRNA therapies are for nonsense mutations only. It has not been explored how tRNAs can be engineered to correct missense mutations. Here, we describe missense-correcting tRNAs (mc-tRNAs) as a potential therapeutic for correcting pathogenic missense mutations. Mc-tRNAs are engineered tRNAs charged with one amino acid, but read codons of another in translation. We first developed a series of fluorescent protein-based reporters that indicate the successful correction of missense mutations via restoration of fluorescence. We engineered mc-tRNAs that effectively corrected serine and arginine missense mutations in the reporters and confirmed the amino acid substitution by mass spectrometry and mc-tRNA expression by sequencing. We examined the transcriptome response to mc-tRNA expression and found some mc-tRNAs induced minimum transcriptomic changes. Furthermore, we applied an mc-tRNA to rescue a pathogenic CAPN3 Arg-to-Gln mutant involved in LGMD2A. These results establish a versatile pipeline for mc-tRNA engineering and demonstrate the potential of mc-tRNA as an alternative therapeutic platform for the treatment of genetic disorders.

A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature

Lymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αβT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency.

Polymerization of recombinant tau core fragments in vitro and seeding studies in cultured cells.

The relative polymerization of specific tau protein cores that define Alzheimer's disease, Pick's disease and corticobasal degeneration were investigated using amyloid fluorometry and electron microscopy. In addition, the relative prion-like activities of polymers comprised of these respective tau protein segments were investigated in a cell-based assay. It is demonstrated that the seeding activities of specific tau core fibrils are affected by the presence of pathogenic tau missense mutations and the microtubule binding domain composition of tau. The unique impact of tau phosphorylation on seeding propensity was also investigated by altering stretches of phospho-mimetic and phospho-null residues in the presence of Alzheimer's disease tau core fibrils. These results have important mechanistic implications for mutation and isoform-specific driven pathogenesis.

Identifying Targeted Therapies for CBFA2T3- GLIS2 Acute Myeloid Leukemia

CBFA2T3- GLIS2 fusion positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. Children with this subtype of AML frequently experience upfront chemoresistance with a high cumulative incidence of relapse (42-83%) and a dismal overall survival (~20%) even with intensive therapy. New treatment approaches are urgently needed. By interrogating the Broad Institute's Cancer Dependency Map (DepMap), a data set composed of genome-scale CRISPR-Cas9 screens in over 1000 cancer cell lines, we discovered that the CBFA2T3- GLIS2 AML model M-07e was highly dependent on the kinase JAK2. Indeed, M-07e was one of the most JAK2 dependent models in the data set. Using the same genome-scale library, we next performed CRISPR-Cas9 screens in WSU-AML and CMS, two additional AML cell lines harboring this fusion, and revealed JAK2 as a strong dependency shared by the 3 cell lines. Using a doxycycline-inducible knockout (KO) system, we validated JAK2 KO by western blot in three AML cell lines and cells from a patient-derived xenograft (PDX) harboring the fusion. Using two different sgRNAs targeting JAK2 (sgJAK2) and a non-targeting (sgNT) control, we validated JAK2 dependency in all 4 AML models in competitive growth assays. We also observed impaired proliferation and induced apoptosis upon JAK2 KO. To evaluate a role for JAK2 dependency in vivo, we intravenously injected NSGS mice with WSU-AML either transduced with doxycycline-inducible sgJAK2 or sgNT. After confirmation of engraftment by bone marrow evaluation, doxycycline chow was initiated. After 2 weeks of doxycycline treatment, we observed a significantly decreased tumor burden in mice with JAK2 KO AML compared to sgNT as measured by a decrement in human CD45% cells: peripheral blood (2.8% versus 12.9%), bone marrow (37.4% versus 56.3%,) and spleen (19% versus 79.5%). We next assessed chemical inhibitors of JAK2. Both the type I JAK2 inhibitor ruxolitinib and the type II JAK2 inhibitor CHZ868 exhibited strong activity in vitro in CBFA2T3- GLIS2 cell lines and PDX cells, many resistant to cytotoxic chemotherapy. Because ruxolitinib is FDA-approved for other indications, we evaluated this drug in a cell line and PDX model of CBFA2T3- GLIS2 AML in vivo. As previously reported in myeloproliferative neoplasms, JAK2 target inhibition with ruxolitinib treatment was incomplete, and accordingly, in vivo response was modest with leukemia ultimately progressing. Evaluation of CHZ868 in vivo is ongoing. Because single agent targeted therapy is typically insufficient for durable response in the treatment of most cancers, we utilized CRISPR-Cas9 anchor screening to identify candidate resistance mechanisms and potential synergistic combinations with JAK2 inhibitors in CMS and WSU-AML cells. We compared the changes in abundance of sgRNAs in the cells either treated with ruxolitinib (IC 50) or vehicle for 14 days. The correlation of hits between the two cell lines was strong, and we found that sgRNAs targeting multiple negative regulators of the MAPK pathway were significantly enriched in the ruxolitinib-treated arm. In parallel, we generated resistant CMS sublines by chronic exposure to ruxolitinib. Ruxolitinib-resistant CMS cells were found to have a pathogenic NRAS missense mutation and an associated increase in levels of phosphorylated MEK. Accordingly, they were responsive to the MEK inhibitor trametinib. Both approaches converge on activation of the MAPK pathway as a resistance mechanism to JAK2 inhibitors in CBFA2T3- GLIS2 AML. We next hypothesized that targeting the MAPK pathway could overcome resistance to JAK2 inhibitors in this disease context. Indeed, treatment with ruxolitinib and the MEK inhibitor trametinib exhibited a synergistic effect when used in combination in cell lines and PDX cells harboring the fusion in vitro with in vivo testing as a next step. In summary, we validated JAK2 as a strong dependency in CBFA2T3- GLIS2 fusion positive pediatric AML. We demonstrated that JAK2 KO or small molecule inhibitors impaired cell viability and induced apoptosis in vitro, and JAK2 KO was highly efficacious in decreasing leukemia burden in vivo. Activation of the MAPK pathway renders resistance to JAK2 inhibitors and the combination of a JAK2 with MEK inhibitor is highly synergistic.

Genomic analysis of a Palestinian family with inherited cancer syndrome: a next-generation sequencing study.

Familial predisposition is a strong risk factor for different types of cancer and accounts for around 10% of the cases. In this study, we investigated cancer predisposition in a Palestinian family using whole-exome sequencing (WES) technologies. In this study, we focused more on cutaneous melanoma (CM). Our analysis identified three heterozygous rare missense variants, WRN (p.L383F and p.A995T) and TYRP1 (p.T262M) and a pathogenic homozygous missense mutation in ERCC2 (p.R683Q). Although WRN and TYRP1 genes and their variations were correlated with different types of cancer, including melanoma, the currently identified WRN and TYRP1 variants were not reported previously in melanoma cases. The pathogenic mutation was segregated with the clinical phenotypes and found in the two affected brothers, one with CM and the other with brain tumor, and was confirmed by Sanger sequencing analysis. Segregation analysis of this mutation revealed that family members are either heterozygous or wild type. Our findings confirm that the homozygous ERCC2 (p.R683Q) mutation was responsible for causing melanoma and other cancer types in the family. Our work highlights the value to decipher the mutational background of familial cancers, especially CM, in the Palestinian population to guide diagnosis, prevention, and treatment of affected patients and their families.

Identification of Pathogenic Missense Mutations in the CHRNA5 Gene: A Computational Approach.

Aim TheCHRNA5/A3/B4gene locus is closely related to nicotine dependence and other smoking-related disorders. Coupling genetic and clinical studies of nicotine dependence and smoking behaviors may open new avenues for medication development. The aim of this study is to investigate the functional missense mutations in the CHRNA5 gene. Methodology The Ensembl database was used to gather data on missense mutations of the human CHRNA5 gene. Computational tools viz. SIFT (Sorting Intolerant From Tolerant), PolyPhen (Polymorphism Phenotyping),PROVEAN (Protein Variation Effect Analyzer), I-Mutant, and MutPred were used to uncover the pathogenic mutations in the gene under investigation. Results Among 161 missense variants reported inthe CHRNA5 gene, 94 variants were found to be highly pathogenic. Moreover, 20 were pathogenic and 4 were not pathogenic. Conclusion The computational analysis disclosed harmful mutations intheCHRNA5 gene which could be potentiallyassociated with smoking-related traits.

A Pathogenic Missense Mutation in Kainate Receptors Elevates Dendritic Excitability and Synaptic Integration through Dysregulation of SK Channels.

Numerous rare variants that cause neurodevelopmental disorders (NDDs) occur within genes encoding synaptic proteins, including ionotropic glutamate receptors. However, in many cases, it remains unclear how damaging missense variants affect brain function. We determined the physiological consequences of an NDD causing missense mutation in the GRIK2 kainate receptor (KAR) gene, that results in a single amino acid change p.Ala657Thr in the GluK2 receptor subunit. We engineered this mutation in the mouse Grik2 gene, yielding a GluK2(A657T) mouse, and studied mice of both sexes to determine how hippocampal neuronal function is disrupted. Synaptic KAR currents in hippocampal CA3 pyramidal neurons from heterozygous A657T mice exhibited slow decay kinetics, consistent with incorporation of the mutant subunit into functional receptors. Unexpectedly, CA3 neurons demonstrated elevated action potential spiking because of downregulation of the small-conductance Ca2+ activated K+ channel (SK), which mediates the post-spike afterhyperpolarization. The reduction in SK activity resulted in increased CA3 dendritic excitability, increased EPSP-spike coupling, and lowered the threshold for the induction of LTP of the associational-commissural synapses in CA3 neurons. Pharmacological inhibition of SK channels in WT mice increased dendritic excitability and EPSP-spike coupling, mimicking the phenotype in A657T mice and suggesting a causative role for attenuated SK activity in aberrant excitability observed in the mutant mice. These findings demonstrate that a disease-associated missense mutation in GRIK2 leads to altered signaling through neuronal KARs, pleiotropic effects on neuronal and dendritic excitability, and implicate these processes in neuropathology in patients with genetic NDDs.SIGNIFICANCE STATEMENT Damaging mutations in genes encoding synaptic proteins have been identified in various neurodevelopmental disorders, but the functional consequences at the cellular and circuit level remain elusive. By generating a novel knock-in mutant mouse, this study examined the role of a pathogenic mutation in the GluK2 kainate receptor (KAR) subunit, a subclass of ionotropic glutamate receptors. Analyses of hippocampal CA3 pyramidal neurons determined elevated action potential firing because of an increase in dendritic excitability. Increased dendritic excitability was attributable to reduced activity of a Ca2+ activated K+ channel. These results indicate that a pathogenic KAR mutation results in dysregulation of dendritic K+ channels, which leads to an increase in synaptic integration and backpropagation of action potentials into distal dendrites.

CPC14 A truly VEXing diagnosis

Abstract A 50-year-old man with a background of prostate cancer was admitted with fever, weight loss, polyarthritis, symptomatic anaemia and raised inflammatory markers. Multiple tender indurated violaceous plaques on the trunk and limbs were suggestive of Sweet syndrome. Skin biopsies revealed a neutrophilic dermal infiltrate and a pandermal vasculitis affecting small vessels. Laboratory screening (including rheumatoid factor, anticyclic citrullinated peptide, antinuclear antibody, antineutrophil cytoplasm antibodies, HIV, hepatitis B and C serology, antiphospholipid antibodies and cryoglobulins) was negative. Upper and lower endoscopies and gastrointestinal biopsies were normal. Biopsy of an axillary lymph node revealed reactive changes only. Computed tomography (CT) of the thorax, abdomen and pelvis showed sacroiliitis. A diffuse low signal on T1-weighted magnetic resonance imaging of his spine was suggestive of conversion of fatty marrow to red marrow. His cutaneous findings resolved fully with oral prednisolone 0.5 mg kg−1; however, he had ongoing transfusion-dependent anaemia and arthritis. Infliximab was started for presumed ankylosing spondylitis by rheumatology without improvement. Six months later, he was readmitted with multifocal ulceration of both feet. Histology demonstrated a leucocytoclastic vasculitis. He developed haemoptysis and chest pain. CT of the thorax showed multifocal, bilateral, ground–glass change consistent with pulmonary vasculitis. Bone marrow biopsy revealed hypercellular marrow with markedly increased granulopoiesis. A pathogenic missense mutation in UBA1 (c121A.G; pMet41Val) was found on next-generation sequencing of the bone marrow aspirate (Leeds Cancer Centre). Somatic variants at this codon have been implicated in vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome (Beck DB, Ferrada MA, Sikora KA et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 2020; 383:2628–38). First described in 2020, VEXAS syndrome is a somatic monogenic autoinflammatory disorder of adulthood. Affected patients develop predominantly inflammatory and haematological symptoms. Cutaneous findings have been reported in up to 89% of cases (Georgin-Lavialle S, Terrier B, Guedon AF et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol 2022; 186:564–74) and include neutrophilic dermatosis, vasculitis, urticaria, angioedema, erythematous papules and chondritis. Systemic manifestations are protean, but fever of noninfectious origin, weight loss, and ocular and pulmonary manifestations are most prevalent. Fifty per cent of patients with VEXAS have myelodysplastic syndrome (Georgin-Lavialle et al.). In our case, persistent haematological abnormalities coupled with multisystem inflammation (arthritis, vasculitis) prompted testing for VEXAS syndrome. This novel condition should be considered when assessing adult patients with neutrophilic dermatosis or cutaneous vasculitis who manifest other autoinflammatory phenomena. He was commenced on tocilizumab but, despite this, has ongoing acral vasculopathy.

PSEN1/SLC20A2 double mutation causes early-onset Alzheimer’s disease and primary familial brain calcification co-morbidity

Primary familial brain calcification (PFBC; formerly Fahr’s disease) and early-onset Alzheimer’s disease (EOAD) may share partially overlapping pathogenic principles. Although the heterozygous loss-of-function mutation c.1523 + 1G > T in the PFBC-linked gene SLC20A2 was detected in a patient with asymmetric tremor, early-onset dementia, and brain calcifications, CSF β-amyloid parameters and FBB-PET suggested cortical β-amyloid pathology. Genetic re-analysis of exome sequences revealed the probably pathogenic missense mutation c.235G > A/p.A79T in PSEN1. The SLC20A2 mutation segregated with mild calcifications in two children younger than 30 years. We thus describe the stochastically extremely unlikely co-morbidity of genetic PFBC and genetic EOAD. The clinical syndromes pointed to additive rather than synergistic effects of the two mutations. MRI data revealed the formation of PFBC calcifications decades before the probable onset of the disease. Our report furthermore exemplifies the value of neuropsychology and amyloid PET for differential diagnosis.

Identifying the Molecular Drivers of Pathogenic Aldehyde Dehydrogenase Missense Mutations in Cancer and Non-Cancer Diseases.

Human aldehyde dehydrogenases (ALDHs) comprising 19 isoenzymes play a vital role on both endogenous and exogenous aldehyde metabolism. This NAD(P)-dependent catalytic process relies on the intact structural and functional activity of the cofactor binding, substrate interaction, and the oligomerization of ALDHs. Disruptions on the activity of ALDHs, however, could result in the accumulation of cytotoxic aldehydes, which have been linked with a wide range of diseases, including both cancers as well as neurological and developmental disorders. In our previous works, we have successfully characterised the structure-function relationships of the missense variants of other proteins. We, therefore, applied a similar analysis pipeline to identify potential molecular drivers of pathogenic ALDH missense mutations. Variants data were first carefully curated and labelled as cancer-risk, non-cancer diseases, and benign. We then leveraged various computational biophysical methods to describe the changes caused by missense mutations, informing a bias of detrimental mutations with destabilising effects. Cooperating with these insights, several machine learning approaches were further utilised to investigate the combination of features, revealing the necessity of the conservation of ALDHs. Our work aims to provide important biological perspectives on pathogenic consequences of missense mutations of ALDHs, which could be invaluable resources in the development of cancer treatment.