Deciphering the dynamics of methicillin-resistant Staphylococcus aureus biofilm formation: from molecular signaling to nanotherapeutic advances.

Methicillin-resistant Staphylococcus aureus (MRSA) represents a global threat, necessitating the development of effective solutions to combat this emerging superbug. In response to selective pressures within healthcare, community, and livestock settings, MRSA has evolved increased biofilm formation as a multifaceted virulence and defensive mechanism, enabling the bacterium to thrive in harsh conditions. This review discusses the molecular mechanisms contributing to biofilm formation across its developmental stages, hence representing a step forward in developing promising strategies for impeding or eradicating biofilms. During staphylococcal biofilm development, cell wall-anchored proteins attach bacterial cells to biotic or abiotic surfaces; extracellular polymeric substances build scaffolds for biofilm formation; the cidABC operon controls cell lysis within the biofilm, and proteases facilitate dispersal. Beside the three main sequential stages of biofilm formation (attachment, maturation, and dispersal), this review unveils two unique developmental stages in the biofilm formation process for MRSA; multiplication and exodus. We also highlighted the quorum sensing as a cell-to-cell communication process, allowing distant bacterial cells to adapt to the conditions surrounding the bacterial biofilm. In S. aureus, the quorum sensing process is mediated by autoinducing peptides (AIPs) as signaling molecules, with the accessory gene regulator system playing a pivotal role in orchestrating the production of AIPs and various virulence factors. Several quorum inhibitors showed promising anti-virulence and antibiofilm effects that vary in type and function according to the targeted molecule. Disrupting the biofilm architecture and eradicating sessile bacterial cells are crucial steps to prevent colonization on other surfaces or organs. In this context, nanoparticles emerge as efficient carriers for delivering antimicrobial and antibiofilm agents throughout the biofilm architecture. Although metal-based nanoparticles have been previously used in combatting biofilms, its non-degradability and toxicity within the human body presents a real challenge. Therefore, organic nanoparticles in conjunction with quorum inhibitors have been proposed as a promising strategy against biofilms. As nanotherapeutics continue to gain recognition as an antibiofilm strategy, the development of more antibiofilm nanotherapeutics could offer a promising solution to combat biofilm-mediated resistance.

Targeting NANOG and FAK via Cx26-derived Cell-penetrating Peptides in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents the most lethal and treatment-resistant breast cancer subtype with limited treatment options. We previously identified a protein complex unique to TNBC composed of the gap junction protein connexin 26 (Cx26), the pluripotency transcription factor NANOG, and focal adhesion kinase (FAK). We sought to determine whether a peptide mimetic of the interaction region of Cx26 attenuated tumor growth in preclinical models. We designed peptides based on Cx26 juxtamembrane domains and performed binding experiments with NANOG and FAK using surface plasmon resonance. Binding studies revealed that the Cx26 C-terminal tail and intracellular loop bound to NANOG and FAK with submicromolar-to-micromolar affinity and that a 5-amino acid sequence in the C-terminal tail of Cx26 (RYCSG) was sufficient for binding. Peptides with high affinity were engineered with a cell-penetrating antennapedia sequence and assessed in functional assays including cell proliferation, tumorsphere formation, and in vivo tumor growth, and downstream signaling changes were measured. The cell-penetrating Cx26 peptide (aCx26-pep) disrupted self-renewal while reducing nuclear FAK and NANOG and inhibiting NANOG target gene expression in TNBC cells but not luminal mammary epithelial cells. In vivo, aCx26-pep reduced tumor growth and proliferation and induced cell death. Here, we provide proof-of-concept that a Cx26 peptide-based strategy inhibits growth and alters NANOG activity specifically in TNBC, indicating the therapeutic potential of this targeting approach.

Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats.

Cancer chemotherapy-induced neuropathic pain is a devastating pain syndrome without effective therapies. We previously reported that rats deficient in complement C3, the central component of complement activation cascade, showed a reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of this model. However, the underlying mechanism was unclear. Complement activation leads to the production of C3a, which mediates inflammation through its receptor C3aR1. In this article, we report that the administration of paclitaxel induced a significantly higher expression level of C3aR1 on dorsal root ganglion (DRG) macrophages and expansion of these macrophages in DRGs in wild-type (WT) compared with in C3aR1 knockout (KO) mice. We also found that paclitaxel induced less severe PIMA, along with a reduced DRG expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4), an essential mediator for PIMA, in C3aR1 KO than in WT mice. Treating WT mice or rats with a C3aR1 antagonist markedly attenuated PIMA in association with downregulated DRG TRPV4 expression, reduced DRG macrophages expansion, suppressed DRG neuron hyperexcitability, and alleviated peripheral intraepidermal nerve fiber loss. Administration of C3aR1 antagonist to TRPV4 KO mice further protected them from PIMA. These results suggest that complement regulates PIMA development through C3aR1 to upregulate TRPV4 on DRG neurons and promote DRG macrophage expansion. Targeting C3aR1 could be a novel therapeutic approach to alleviate this debilitating pain syndrome.

Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase.

Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression. SIGNIFICANCE: The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.

Entwined African and Asian genetic roots of medieval peoples of the Swahili coast.

The urban peoples of the Swahili coast traded across eastern Africa and the Indian Ocean and were among the first practitioners of Islam among sub-Saharan people1,2. The extent to which these early interactions between Africans and non-Africans were accompanied by genetic exchange remains unknown. Here we report ancient DNA data for 80 individuals from 6 medieval and early modern (AD 1250-1800) coastal towns and an inland town after AD 1650. More than half of the DNA of many of the individuals from coastal towns originates from primarily female ancestors from Africa, with a large proportion-and occasionally more than half-of the DNA coming from Asian ancestors. The Asian ancestry includes components associated with Persia and India, with 80-90% of the Asian DNA originating from Persian men. Peoples of African and Asian origins began to mix by about AD 1000, coinciding with the large-scale adoption of Islam. Before about AD 1500, the Southwest Asian ancestry was mainly Persian-related, consistent with the narrative of the Kilwa Chronicle, the oldest history told by people of the Swahili coast3. After this time, the sources of DNA became increasingly Arabian, consistent with evidence of growing interactions with southern Arabia4. Subsequent interactions with Asian and African people further changed the ancestry of present-day people of the Swahili coast in relation to the medieval individuals whose DNA we sequenced.

Characterization and Biodegradation of Phenol by Pseudomonas aeruginosa and Klebsiella variicola Strains Isolated from Sewage Sludge and Their Effect on Soybean Seeds Germination.

Phenols are very soluble in water; as a result, they can pollute a massive volume of fresh water, wastewater, groundwater, oceans, and soil, negatively affecting plant germination and animal and human health. For the detoxification and bioremediation of phenol in wastewater, phenol biodegradation using novel bacteria isolated from sewage sludge was investigated. Twenty samples from sewage sludge (SS) were collected, and bacteria in SS contents were cultured in the mineral salt agar (MSA) containing phenol (500 mg/L). Twenty colonies (S1 up to S20) were recovered from all the tested SS samples. The characteristics of three bacterial properties, 16S rDNA sequencing, similarities, GenBank accession number, and phylogenetic analysis showed that strains S3, S10, and S18 were Pseudomonas aeruginosa, Klebsiella pneumoniae, and Klebsiella variicola, respectively. P. aeruginosa, K. pneumoniae, and K. variicola were able to degrade 1000 mg/L phenol in the mineral salt medium. The bacterial strains from sewage sludge were efficient in removing 71.70 and 74.67% of phenol at 1000 mg/L within three days and could tolerate high phenol concentrations (2000 mg/L). The findings showed that P. aeruginosa, K. pneumoniae, and K. variicola could potentially treat phenolic water. All soybean and faba bean seeds were germinated after being treated with 250, 500, 750, and 1000 mg/L phenol in a mineral salt medium inoculated with these strains. The highest maximum phenol removal and detoxification rates were P. aeruginosa and K. variicola. These strains may help decompose and detoxify phenol from industrial wastewater with high phenol levels and bioremediating phenol-contaminated soils.

Genomic alterations impact cell cycle-related genes during prostate cancer progression.

The recent genomic characterization of patient specimens has started to reveal the landscape of somatic alterations in clinical prostate cancer (CaP) and its association with disease progression and treatment resistance. The extent to which such alterations impact hallmarks of cancer is still unclear. Here, we interrogate genomic data from thousands of clinical CaP specimens that reflect progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP for alterations in cell cycle-associated and -regulated genes, which are central to cancer initiation and progression. We evaluate gene signatures previously curated to evaluate G1-S and G2-M phase transitions or to represent the cell cycle-dependent proteome. The resulting CaP (stage)-specific overview confirmed the presence of well-known driver alterations impacting, for instance, the genes encoding p53 and MYC, and uncovered novel previously unrecognized mutations that affect others such as the PKMYT1 and MTBP genes. The cancer dependency and drugability of representative genomically altered cell cycle determinants were verified also. Taken together, these analyses on hundreds of often less-characterized cell cycle regulators expand considerably the scope of genomic alterations associated with CaP cell proliferation and cell cycle and isolate such regulatory proteins as putative drivers of CaP treatment resistance and entirely novel therapeutic targets for CaP therapy.

Novel insights in cell cycle dysregulation during prostate cancer progression.

Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators and address challenges and limitations in the approaches modulating their action for CaP treatment.

Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes.

BACKGROUND: Metastatic prostate cancer (CaP) treatments are evolving rapidly but without evidence-based biomarkers to predict responses, and to maximize remissions and survival. OBJECTIVE: To determine the activity of androgen receptor (AR), the target for default first-line systemic treatment, in localized treatment-naïve CaP and its association with clinical risk factors, molecular markers, CaP subtypes, and predictors of treatment response. DESIGN SETTING AND PARTICIPANTS: We examined 452 bona fide AR target genes in clinical-grade expression profiles from 6532 such CaPs collected between 2013 and 2017 by US physicians ordering the Decipher RP test. Results were validated in three independent smaller cohorts (n = 73, 90, and 127) and clinical CaP AR ChIP-Seq data. Association with CaP differentiation and progression was analyzed in independent datasets. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Unsupervised clustering of CaPs based on AR target gene expression was aligned with clinical variables, differentiation scores, molecular subtypes, and predictors of response to hormonal therapy, radiotherapy, and chemotherapy. AR target gene sets were analyzed via Gene Set Enrichment Analysis for differentiation and treatment resistance, Ingenuity Pathway Analysis for associated biology, and Cistrome for genomic AR binding site (ARBS) composition. RESULTS AND LIMITATIONS: Expression of eight AR target gene subsignatures gave rise to five CaP clusters, which were preferentially associated with CaP molecular subtypes, differentiation, and predictors of treatment response rather than with clinical variables. Subsignatures differed in contribution to CaP progression, luminal/basal differentiation, CaP biology, and ARBS composition. Validation in prospective trials and optimized quantitation are needed for clinical implementation. CONCLUSIONS: Measurement of AR activity patterns in treatment-naïve CaP may serve as a first branch of an evidence-based decision tree to optimize personalized treatment plans. PATIENT SUMMARY: Treatment options for metastatic prostate cancer are increasing without information needed to choose the right treatment for the right patient. We found variation in the behavior of the target for the default first-line therapy before treatment, which may help optimize treatment plans.

AR-dependent phosphorylation and phospho-proteome targets in prostate cancer.

Prostate cancer (CaP) is the second leading cause of cancer-related deaths in Western men. Because androgens drive CaP by activating the androgen receptor (AR), blocking AR's ligand activation, known as androgen deprivation therapy (ADT), is the default treatment for metastatic CaP. Despite an initial remission, CaP eventually develops resistance to ADT and progresses to castration-recurrent CaP (CRPC). CRPC continues to rely on aberrantly activated AR that is no longer inhibited effectively by available therapeutics. Interference with signaling pathways downstream of activated AR that mediate aggressive CRPC behavior may lead to alternative CaP treatments. Developing such therapeutic strategies requires a thorough mechanistic understanding of the most clinically relevant and druggable AR-dependent signaling events. Recent proteomics analyses of CRPC clinical specimens indicate a shift in the phosphoproteome during CaP progression. Kinases and phosphatases represent druggable entities, for which clinically tested inhibitors are available, some of which are incorporated already in treatment plans for other human malignancies. Here, we reviewed the AR-associated transcriptome and translational regulon, and AR interactome involved in CaP phosphorylation events. Novel and for the most part mutually exclusive AR-dependent transcriptional and post-transcriptional control over kinase and phosphatase expression was found, with yet other phospho-regulators interacting with AR. The multiple mechanisms by which AR can shape and fine-tune the CaP phosphoproteome were reflected in diverse aspects of CaP biology such as cell cycle progression and cell migration. Furthermore, we examined the potential, limitations and challenges of interfering with AR-mediated phosphorylation events as alternative strategy to block AR function during CaP progression.

Protein Kinase N1 control of androgen-responsive serum response factor action provides rationale for novel prostate cancer treatment strategy.

Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a siRNA screen and candidate gene approach, RNA-Seq studies confirmed that the RhoA effector Protein Kinase N1 (PKN1) transduces androgen-responsiveness to SRF. Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively, androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1's effects on SRF relied on its kinase domain. The multikinase inhibitor lestaurtinib inhibited PKN1 action and preferentially affected androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants, lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR's transcriptional output to inhibit CaP growth.

Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus.

BACKGROUND: Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern. METHODS: In this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism. RESULTS: Whole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing. CONCLUSIONS: The compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases.

Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.

BACKGROUND: Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. METHODS: In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ~490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C ß 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP2) to inositol 1,4,5 triphosphate (IP3) and diacylglycerol. RESULTS: The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. CONCLUSIONS: Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).

Breast Arterial Calcifications on Mammography Do Not Predict Myocardial Ischemia on Myocardial Perfusion Single-Photon Emission Computed Tomography.

BACKGROUND: The aim of this study was to determine if breast arterial calcification (BAC) on mammography predicts myocardial ischemia (MI) on stress myocardial perfusion single-photon emission computed tomography (MPS). BAC is a type of medial artery calcification that can be seen incidentally on mammography, but the relationship between coronary artery calcification and MI on MPS is yet unknown. METHODS: A total of 435 consecutive women underwent mammography and stress MPS within 1 year of each other. BAC was quantitatively evaluated (0 - 13). Patients with known coronary artery diseases (CADs) such as coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), MI, positive coronary angiogram or positive MPS were excluded from the study. Risk factors for CAD were obtained from a chart review. RESULTS: The mean age was 58 ± 8 years. BAC was found in 258 (59%) of the study population. BAC-positive patients were significantly older than BAC-negative patients (P < 0.0001), there were strong associations between BAC and hypertension (P = 0.0309), chronic kidney disease (CKD) (P = 0.0001), and diabetes (P = 0.0309), but there were significant associations between BACV and hyperlipidemia, family history of CAD, and smoking (P = 0.6856, P = 0.9642, and P = 0.087, respectively). The mean score of BAC was 5 ± 5 in patients with normal MPS and was 6 ± 6 in patients with abnormal MPS. There were no associations between total BAC and MPS results (P = 0.2095), and between BAC categories and MPS result (P = 0.3069). CONCLUSIONS: Based on our study, the presence and severity of BAC on screening or diagnostic mammography do not predict MI on stress MPS, and further cardiac workup based on the presence of BAC is not warranted. BAC is very common in mammography up to 59% and associated with age, diabetes, CKD, and hypertension. In contrast, the prevalence of MI is only 13% in women with BAC and associated with age, diabetes, CKD, hyperlipidemia, and impaired left ventricular function.

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer.

Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0-57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.

A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement.

BACKGROUND: The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. RESULTS: We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c.1423 + 2 T > A) in ELAC2 gene that disrupted the canonical donor splice site of intron 15 of all known isoforms. A noticeable reduction in ELAC2 expression was observed in patients compared to controls. In addition, patients exhibited significantly increased levels of 5' end unprocessed mt-RNAs compared to the control fibroblast cells. CONCLUSIONS: The only three previously reported families with defects in ELAC2 gene exhibited infantile hypertrophic cardiomyopathy and complex I deficiency. In contrast, our patients exhibited intellectual disability as the main feature with minimal cardiac involvement. Therefore our findings expand the phenotypic spectrum of ELAC2- associated disorders illustrating clinical heterogeneity of mutations in this gene. In addition, ELAC2 mutations should be considered when evaluating patient with mainly intellectual disability phenotypes.

A recessive syndrome of intellectual disability, moderate overgrowth, and renal dysplasia predisposing to Wilms tumor is caused by a mutation in FIBP gene.

Clinical classification of overgrowth syndromes represents a challenge since a wide spectrum of disorders result in marked overgrowth. Therefore, there is a continuous effort to identify the genetic basis of these disorders that will eventually facilitate their molecular classification. Here, we have identified the genetic etiology and the pathogenetic mechanism underlying a rare autosomal recessive overgrowth syndrome in three affected siblings. The overgrowth phenotype in the patients was accompanied by developmental delay, learning disabilities, and variable congenital abnormalities. To elucidate the genetic etiology of the disorder, whole-genome genotyping and whole-exome sequencing were used. The disease was mapped to 3p21.1-p14.2 and 11q13.1-q13.4, where an in-frame insertion (c.175_176insTAA) in FIBP gene was revealed. The resulting indel (p.H59LN) was predicted to change the protein conformation with likely deleterious effect on its function as one of the fibroblast growth factor signaling mediators. In vitro cellular proliferation assay and in situ hypridization in vivo were then performed to understand the pathophysiology of the disease. The patients' skin fibroblasts showed an increased proliferation capacity compared to the controls' explaining the observed overgrowth phenotype. In addition, we detected Fibp expression most notably in the brains of mice embryos suggesting a possible effect on cognitive functions early in development. To date, only one patient has been reported with a homozygous nonsense mutation in FIBP exhibiting an overgrowth syndrome with multiple congenital abnormalities. Taken all together, these findings provide convincing evidence implicating FIBP aberrations in the newly recognized overgrowth syndrome and expand the associated phenotypes to include possible Wilms tumor predisposition. © 2016 Wiley Periodicals, Inc.

Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child.

Intellectual disability (ID) is a major public health burden on most societies with significant socioeconomic costs. It has been shown that genetic mutations in numerous genes are responsible for a proportion of hereditary forms of ID. NOP2/Sun transfer RNA (tRNA) methyltransferase family member 2 encoded by NSUN2 gene is a highly conserved protein and has been shown to cause autosomal recessive ID type 5 (MRT5). In this study, we recruited an Emirati consanguineous family with a patient diagnosed with ID. Whole-exome sequencing revealed a homozygous variant c.1020delA in NSUN2 gene. The variants segregated in an autosomal recessive mode of inheritance in the family. This variant is novel and causes a frameshift and premature stop codon. At the messenger RNA (mRNA) level, relative expression analysis showed a decreased level of NSUN2 mRNA in the affected child compared to a healthy individual. Mutation prediction analysis and clinical investigation confirmed the pathogenic nature of the identified variant. We therefore conclude that c.1020delA mutation in NSUN2 is most likely the cause of ID in our patient.