UV Irradiation Induces a Non-coding RNA that Functionally Opposes the Protein Encoded by the Same Gene.

The transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from expression of long mRNAs to shorter isoforms, incorporating alternative last exons (ALEs) that are more proximal to the transcription start site. Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ALE isoform of which the RNA, rather than an encoded protein, is critical for the eventual recovery of transcription. The non-coding ASCC3 isoform counteracts the function of the protein-coding isoform, indicating crosstalk between them. Thus, the ASCC3 gene expresses both coding and non-coding transcript isoforms with opposite effects on transcription recovery after UV-induced DNA damage.

Aberrant RNA methylation triggers recruitment of an alkylation repair complex.

Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvious. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. In turn, recruitment of ASCC during alkylation damage, which is mediated by the E3 ubiquitin ligase RNF113A, suppresses transcription and R-loop formation. We further show that alkylated pre-mRNA is sufficient to activate RNF113A E3 ligase in vitro in a manner dependent on its RNA binding Zn-finger domain. Together, our work identifies an unexpected role for RNA damage in eliciting a specific response to genotoxins.

Translation stress and collided ribosomes are co-activators of cGAS.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to activate the innate immune system. Here, we report the unexpected discovery that cGAS also senses dysfunctional protein production. Purified ribosomes interact directly with cGAS and stimulate its DNA-dependent activity in vitro. Disruption of the ribosome-associated protein quality control (RQC) pathway, which detects and resolves ribosome collision during translation, results in cGAS-dependent ISG expression and causes re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and orthogonal perturbations that result in elevated levels of collided ribosomes and RQC activation cause sub-cellular re-localization of cGAS and ribosome binding in vivo as well. Thus, translation stress potently increases DNA-dependent cGAS activation. These findings have implications for the inflammatory response to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.

The ASC-1 Complex Disassembles Collided Ribosomes.

Translating ribosomes that slow excessively incur collisions with trailing ribosomes. Persistent collisions are detected by ZNF598, a ubiquitin ligase that ubiquitinates sites on the ribosomal 40S subunit to initiate pathways of mRNA and protein quality control. The collided ribosome complex must be disassembled to initiate downstream quality control, but the mechanistic basis of disassembly is unclear. Here, we reconstitute the disassembly of a collided polysome in a mammalian cell-free system. The widely conserved ASC-1 complex (ASCC) containing the ASCC3 helicase disassembles the leading ribosome in an ATP-dependent reaction. Disassembly, but not ribosome association, requires 40S ubiquitination by ZNF598, but not GTP-dependent factors, including the Pelo-Hbs1L ribosome rescue complex. Trailing ribosomes can elongate once the roadblock has been removed and only become targets if they subsequently stall and incur collisions. These findings define the specific role of ASCC during ribosome-associated quality control and identify the molecular target of its activity.

The ASC-1 complex promotes translation initiation by scanning ribosomes.

Translation initiates when the eIF4F complex binds the 5' mRNA cap, followed by 5' untranslated region scanning for the start codon by scanning ribosomes. Here, we demonstrate that the ASC-1 complex (ASCC), which was previously shown to promote the dissociation of colliding 80S ribosomes, associates with scanning ribosomes to regulate translation initiation. Selective translation complex profiling (TCP-seq) analysis revealed that ASCC3, a helicase domain-containing subunit of ASCC, localizes predominantly to the 5' untranslated region of mRNAs. Ribo-seq, TCP-seq, and luciferase reporter analyses showed that ASCC3 knockdown impairs 43S preinitiation complex loading and scanning dynamics, thereby reducing translation efficiency. Whereas eIF4A, an RNA helicase in the eIF4F complex, is important for global translation, ASCC was found to regulate the scanning process for a specific subset of transcripts. Our results have thus revealed that ASCC is required not only for dissociation of colliding 80S ribosomes but also for efficient translation initiation by scanning ribosomes at a subset of transcripts.

A common [18F]-FDG PET radiomic signature to predict survival in patients with HPV-induced cancers.

Locally advanced cervical cancer (LACC) and anal and oropharyngeal squamous cell carcinoma (ASCC and OPSCC) are mostly caused by oncogenic human papillomaviruses (HPV). In this paper, we developed machine learning (ML) models based on clinical, biological, and radiomic features extracted from pre-treatment fluorine-18-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) images to predict the survival of patients with HPV-induced cancers. For this purpose, cohorts from five institutions were used: two cohorts of patients treated for LACC including 104 patients from Gustave Roussy Campus Cancer (Center 1) and 90 patients from Leeds Teaching Hospitals NHS Trust (Center 2), two datasets of patients treated for ASCC composed of 66 patients from Institut du Cancer de Montpellier (Center 3) and 67 patients from Oslo University Hospital (Center 4), and one dataset of 45 OPSCC patients from the University Hospital of Zurich (Center 5). Radiomic features were extracted from baseline [18F]-FDG PET images. The ComBat technique was applied to mitigate intra-scanner variability. A modified consensus nested cross-validation for feature selection and hyperparameter tuning was applied on four ML models to predict progression-free survival (PFS) and overall survival (OS) using harmonized imaging features and/or clinical and biological variables as inputs. Each model was trained and optimized on Center 1 and Center 3 cohorts and tested on Center 2, Center 4, and Center 5 cohorts. The radiomic-based CoxNet model achieved C-index values of 0.75 and 0.78 for PFS and 0.76, 0.74, and 0.75 for OS on the test sets. Radiomic feature-based models had superior performance compared to the bioclinical ones, and combining radiomic and bioclinical variables did not improve the performances. Metabolic tumor volume (MTV)-based models obtained lower C-index values for a majority of the tested configurations but quite equivalent performance in terms of time-dependent AUCs (td-AUC). The results demonstrate the possibility of identifying common PET-based image signatures for predicting the response of patients with induced HPV pathology, validated on multi-center multiconstructor data.

Congenital myopathy as a new phenotype caused by two undescribed variants in ASCC1 gene.

We present a patient with congenital myopathy and an inborn epiphysiolysis of the ulna. Whole-exome sequencing analysis revealed two novel mutations in Activation Signal Cointegrator Complex 1 (ASCC1) gene in a compound heterozygous state-a splicing variant c.395-2A>G and a deletion of the first two coding exons. Homozygous and compound heterozygous LoF variants in ASCC1 gene lead to a severe phenotype of spinal muscular atrophy with congenital bone fractures 2 (SMABF2). All patients described to date presented with a severe muscular hypotony, inborn fractures, and passed away shortly after birth while our proband had moderate hypotony, no fractures, but epiphysiolysis and he was 3.5 years old at the time of examination. To explain the phenotype of our patient, we performed an RNA analysis of all family members. We discovered that the c.395-2A>G variant results in two aberrant mRNA isoforms. We also validated the deletion of two exons in ASCC1 gene that lead to the increased expression of this truncated transcript by 1.8 times. To investigate the possible impact of this deletion on the phenotype we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated protein with shortened KH domain and a full RNA ligase-like domain. We suggest that this unexpectedly different phenotype of the proband with ASCC1-related disorder could be explained by the presence of the truncated protein with an increased expression.

ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA.

BACKGROUND: Reversible enzymatic methylation of mammalian mRNA is widespread and serves crucial regulatory functions, but little is known to what degree chemical alkylators mediate overlapping modifications and whether cells distinguish aberrant from canonical methylations. METHODS: Here we use quantitative mass spectrometry to determine the fate of chemically induced methylbases in the mRNA of human cells. Concomitant alteration in the mRNA binding proteome was analyzed by SILAC mass spectrometry. RESULTS: MMS induced prominent direct mRNA methylations that were chemically identical to endogenous methylbases. Transient loss of 40S ribosomal proteins from isolated mRNA suggests that aberrant methylbases mediate arrested translational initiation and potentially also no-go decay of the affected mRNA. Four proteins (ASCC3, YTHDC2, TRIM25 and GEMIN5) displayed increased mRNA binding after MMS treatment. ASCC3 is a binding partner of the DNA/RNA demethylase ALKBH3 and was recently shown to promote disassembly of collided ribosomes as part of the ribosome quality control (RQC) trigger complex. We find that ASCC3-deficient cells display delayed removal of MMS-induced 1-methyladenosine (m1A) and 3-methylcytosine (m3C) from mRNA and impaired formation of MMS-induced P-bodies. CONCLUSIONS: Our findings conform to a model in which ASCC3-mediated disassembly of collided ribosomes allows demethylation of aberrant m1A and m3C by ALKBH3. Our findings constitute first evidence of selective sanitation of aberrant mRNA methylbases over their endogenous counterparts and warrant further studies on RNA-mediated effects of chemical alkylators commonly used in the clinic.

Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2).

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.

Cisplatin/capecitabine with intensity-modulated radiation therapy in anal squamous cell carcinoma: a preliminary study.

OBJECTIVE: Mitomycin (MMC)/5-fluoroural (5-FU) with concurrent radiation is the standard treatment of anal squamous cell carcinoma (ASCC). The aim of this study is to evaluate the efficacy and safety of cisplatin/capecitabine (XP) as an alternative with intensity-modulated radiation therapy (IMRT) in ASCC setting. METHODS: We retrospectively screened all patients with stage I-IV ASCC from January 2010 to June 2019. The records of patients who received definitive chemoradiation with cisplatin/capecitabine (XP) and IMRT were collected and analyzed. RESULTS: The first patient was treated with XP in 2017, so totally 11 patients were included in our study from January 2017 to June 2019. All patients have experienced clinical complete response (cCR). After a median follow-up of 30 months (range, 18-39 months), no patient had local recurrence or distant metastasis. Two-year colostomy-free survival (CFS) and two-year disease-free survival (DFS) were both 100%. The median overall survival (OS) has not reached. Grade 3 acute toxicities included leukopenia (1, 9.1%), neutropenia (2, 18.2%) and thrombocytopenia (2, 18.2%). No grade 4 acute adverse events occurred. CONCLUSION: In our study, cisplatin/capecitabine combined with IMRT was safe in ASCC patients, with favorable efficacy as an alternative, and is expected to be explored in study with larger sample.

Inherited Defects of the ASC-1 Complex in Congenital Neuromuscular Diseases.

Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent identification of mutations in the TRIP4 and ASCC1 genes, encoding, respectively, ASC-1 and ASCC1, two subunits of the ASC-1 (Activating Signal Cointegrator-1) complex. This complex is a poorly known transcriptional coregulator involved in transcriptional, post-transcriptional or translational activities. Inherited defects in components of the ASC-1 complex have been associated with several autosomal recessive phenotypes, including severe and mild forms of striated muscle disease (congenital myopathy with or without myocardial involvement), but also cases diagnosed of motor neuron disease (spinal muscular atrophy). Additionally, antenatal bone fractures were present in the reported patients with ASCC1 mutations. Functional studies revealed that the ASC-1 subunit is a novel regulator of cell cycle, proliferation and growth in muscle and non-muscular cells. In this review, we summarize and discuss the available data on the clinical and histopathological phenotypes associated with inherited defects of the ASC-1 complex proteins, the known genotype-phenotype correlations, the ASC-1 pathophysiological role, the puzzling question of motoneuron versus primary muscle involvement and potential future research avenues, illustrating the study of rare monogenic disorders as an interesting model paradigm to understand major physiological processes.

A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1.

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) is a rare autosomal recessive neuromuscular disorder characterized by arthrogryposis multiplex congenita and prenatal fractures of the long bones, with poor prognosis. The most affected patients present with biallelic loss-of-function nucleotide variants in ASCC1 gene, coding a subunit of the transcriptional coactivator ASC-1 complex, although the exact pathogenesis is yet unknown. This work describes the first case of SMABF2 in a stillbirth with documented evolution of the disease in the prenatal period. A microdeletion copy number variant (CNV) of about 64 Kb, involving four exons of ASCC1, was firstly detected by microarray analysis, requested for arthrogryposis and hydrops. Subsequent exome analysis disclosed a nucleotide variant of the same gene [c.1027C>T; (p. Arg343*)], resulting in the introduction of a premature termination codon. This stillbirth represents the first case of ASCC1 compound heterozygosity, due to an exonic microdeletion and a nucleotide variant, expanding the mutational spectrum of this gene. It also provides further evidence that exonic CNVs are an underestimated cause of disease-alleles and that the integrated use of the last generation genetic analysis tools, together with careful clinical evaluations, are fundamental for the characterization of rare diseases even in the prenatal setting.

Association between non-Caucasian-specific ASCC1 gene polymorphism and osteoporosis and obesity in Korean postmenopausal women.

INTRODUCTION: Osteoporosis is a common disorder characterized by decreased bone mineral density (BMD). Interestingly, osteoporosis and obesity have several similar features, including a genetic predisposition and a common bone marrow stem cell. With aging, the composition of bone marrow shifts to adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. MATERIALS AND METHODS: We performed a genome-wide association study (GWAS) analysis with osteoporosis and body mass index (BMI) and did identify an association in 349 and 384 SNPs by filtering with the significant p values (p < 0.001) of BMI and osteoporosis, respectively. RESULTS: Only three of those SNPs were common (rs2326365, rs7097028, and rs11000205) between the SNPs significantly associated with BMI and/or osteoporosis in Korean Association REsource (KARE) females. Two of the three SNPs belonged to the ASCC1 gene and one to the FAM50B gene. We carried out a minor allele frequency (MAF) analysis of the rs7097028 and rs11000205 SNPs in the ASCC1 gene with a geographic genome variant browser. Both rs7097028 and rs11000205 in the ASCC1 gene were seen mostly in African and Southeast Asian populations. CONCLUSIONS: Our results suggest that the ASCC1 gene is a significant genetic factor for determining the risk for both osteoporosis and obesity in KARE postmenopausal females.

Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures.

BACKGROUND: The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder. OBJECTIVE: We aim to contribute to a better understanding of the ASCC1-related disorder. METHODS: Here, we provide a clinical, histological and genetic description of three additional ASCC1 families. RESULTS: All patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations. CONCLUSION: Overall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.

Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures.

Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system.

Prediction of outcome in anal squamous cell carcinoma using radiomic feature analysis of pre-treatment FDG PET-CT.

PURPOSE: Incidence of anal squamous cell carcinoma (ASCC) is increasing, with curative chemoradiotherapy (CRT) as the primary treatment of non-metastatic disease. A significant proportion of patients have locoregional treatment failure (LRF), but distant relapse is uncommon. Accurate prognostication of progression-free survival (PFS) would help personalisation of CRT regimens. The study aim was to evaluate novel imaging pre-treatment features, to prognosticate for PFS in ASCC. METHODS: Consecutive patients with ASCC treated with curative intent at a large tertiary referral centre who underwent pre-treatment FDG-PET/CT were included. Radiomic feature extraction was performed using LIFEx software on baseline FDG-PET/CT. Outcome data (PFS) was collated from electronic patient records. Elastic net regularisation and feature selection were used for logistic regression model generation on a randomly selected training cohort and applied to a validation cohort using TRIPOD guidelines. ROC-AUC analysis was used to compare performance of a regression model encompassing standard clinical prognostic factors (age, sex, tumour and nodal stage-model A), a radiomic feature model (model B) and a combined radiomic/clinical model (model C). RESULTS: A total of 189 patients were included in the study, with 145 in the training cohort and 44 in the validation cohort. Median follow-up was 35.1 and 37. 9 months, respectively for each cohort, with 70.3% and 68.2% reaching this time-point with PFS. GLCM entropy (a measure of randomness of distribution of co-occurring pixel grey-levels), NGLDM busyness (a measure of spatial frequency of changes in intensity between nearby voxels of different grey-level), minimum CT value (lowest HU within the lesion) and SMTV (a standardized version of MTV) were selected for inclusion in the prognostic model, alongside tumour and nodal stage. AUCs for performance of model A (clinical), B (radiomic) and C (radiomic/clinical) were 0.6355, 0.7403, 0.7412 in the training cohort and 0.6024, 0.6595, 0.7381 in the validation cohort. CONCLUSION: Radiomic features extracted from pre-treatment FDG-PET/CT in patients with ASCC may provide better PFS prognosis than conventional staging parameters. With external validation, this might be useful to help personalise CRT regimens in the future.

The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement.

Next-generation sequencing technology aided the identification of the underlying genetic cause in a female newborn with a severe neuromuscular disorder. The patient presented generalized hypotonia, congenital bone fractures, lack of spontaneous movements and poor respiratory effort. She died within the first days of life. Karyotyping and screening for several genes related with neuromuscular diseases all tested negative. A male sibling was subsequently born with the same clinical presentation. Whole-exome sequencing was performed with variant filtering assuming a recessive disease model. Analysis focused on genes known to be related firstly with congenital myopathies, extended to muscle diseases and finally to other neuromuscular disorders. No disease-causing variants were identified. A similar disorder was described in patients with recessive variants in two genes: TRIP4 (three families) and ASCC1 (one family), both encoding subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. Our patient was also found to have a homozygous frameshift variant (c.157dupG, p.Glu53Glyfs*19) in ASCC1 , thereby representing the second known case. This confirms ASCC1 involvement in a severe neuromuscular disease lying within the spinal muscular atrophy or primary muscle disease spectra.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

PURPOSE: To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). METHOD AND MATERIALS: All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. RESULTS: ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. CONCLUSION: The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Case report: Second report of neuromuscular syndrome caused by biallelic variants in ASCC3.

Introduction: Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has been implicated in the pathogenesis of neurodevelopmental disorders and neuromuscular diseases (MIM: 620700). This paper analyzes the clinical manifestations of three patients with developmental delay caused by ASCC3 genetic variation. Additionally, we discuss the previously reported clinical features of these patients along with our own findings, thereby enhancing our understanding of these genetic disorders and providing valuable insights into diagnosis, treatment, and potential interventions for affected individuals. Methods: In this study, we utilized trio-whole-exome sequencing (Trio-WES) and trio-copy number variations sequencing (Trio-CNV-seq) to analyze three unique families diagnosed with developmental delay caused by variation in ASCC3. Additionally, we retrospectively examined eleven previously reported ASCC3 genetic variations exhibiting similar clinical features. Results: Proband I (family 1) and Proband III (family 3) exhibited global developmental delays, characterized by intellectual disability, motor impairment, language retardation, lower muscle strength, and reduced muscle tone in their extremities. Proband II (family 2) presented poor response and dysphagia during feeding within 7 days after birth, clinical examination displayed short limbs, long trunk proportions, and clenched fists frequently observed alongside high muscle tone in his limbs -all indicative signs of developmental delay. Trio-WES revealed compound heterozygous variants in ASCC3 inherited from their parents. Proband I carried c. [489 dup]; [1897C>T], proband II carried c. [2314C>T]; [5002T>A], and proband III carried c. [5113G>T]; [718delG] variations, respectively. Conclusion: This study present the first report of Chinese children carrying compound heterozygous genetic variants in ASCC3 with LOF variants, elucidating the relationship between these variants and various aspects of intellectual disability. This novel finding expands the existing spectrum of ASCC3 variations.

Clinical, Dermoscopic, and Molecular Features of Acantholytic Squamous Cell Carcinoma: A Systematic Review.

INTRODUCTION: Acantholytic squamous cell carcinoma (aSCC) is a rare clinicopathological subtype of cutaneous squamous cell carcinoma, accounting for approximately 4.9% of all SCC cases. However, there are currently no standardized criteria for the diagnosis of aSCC. This systematic review is the first to summarize the clinical and molecular features of aSCC. METHODS: A systematic search of Medline, Embase, Scopus, and PubMed was performed. All articles in English or French were included, with no restriction of publication date. All articles with original data pertaining to clinical or molecular characteristics of aSCC were included. Two reviewers screened articles and resolved conflicts. RESULTS: Our systematic review included 52 studies on the clinical and molecular features of aSCC, including a total of 482 patients (76% male, mean age at diagnosis 68.9 years): 430 cases assessed clinical features, while 149 cases assessed molecular features. The most common location of aSCC was the head and neck (n = 329/430; 76.5%). In terms of morphology, most lesions were described as nodules (n = 93/430, 21.6%), with common surface changes being hyperkeratosis (n = 6), erosion (n = 6), ulceration (n = 5), and crusting (n = 3). With regard to dermoscopy, only six cases were noted in the literature, including findings such as ulceration (n = 3), keratin clots (n = 2), and erosions (n = 2). Thirty-four studies discussed the molecular markers of aSCC, with the most prevalent markers being cytokeratins. CD15 negativity was noted in 23 cases, while common endothelial vascular markers such as CD34 (n = 16), CD31 (n = 15), factor VIII-related antigen (n = 10), and ERG (n = 1) were often not expressed. Finally, expression of intracellular adhesion molecules (i.e., E-cadherin, CD138) was markedly decreased compared to non-acantholytic invasive SCC. CONCLUSIONS: This systematic review summarizes the clinical characteristics and molecular features of aSCC. As clinical differentiation can be difficult, clinicopathological correlation with molecular markers may help ensure proper diagnosis.