Werner (WRN) helicase belongs to the RECQL class of DNA helicases. Mutation in Werner (WRN) RECQL helicase leads to premature aging syndrome, Werner syndrome (WS), and predisposition to multiple cancers. WS patients exhibit heightened incidence of neoplasia, e.g., soft tissue sarcoma, osteosarcoma, malignant melanoma, meningioma, thyroid cancer, breast cancer, and leukemias. Extensive research on WRN helicase has revealed its important and diverse roles in DNA repair pathways, especially in double-strand break repair. Consequently, WRN deficiency is causally associated with genomic instability and cancer predispositions. In this review, we summarize recent studies unraveling the fundamental roles WRN helicase plays in DNA repair and genome stability and its implications in cancer therapy and resistance.
The potentially powerful impact of microbiota has attracted much attention. For example, dysbiosis of the gut microbiota could be linked to various cancers. It is probable that DNA damage and DNA repair impairment due to inflammation from gut dysbiosis would be of importance in carcinogenesis and/or preventing carcinogenesis. In fact, the signature of the gut microbiome has been shown to be associated with responses and/or successful survival rate to certain immune-blockade therapy in several cancers. Conversely, living cells have to cope with the danger of reactive oxygen species (ROS) disturbing the integrity of biomolecules, which can eventually lead to carcinogenesis if otherwise untreated. Gut microbiota could modulate considerable levels of ROS and oxidative damage. Interestingly, an anti-proliferative family (APRO) characterized by several immediate early responsive gene products might be deeply involved in the mechanism of carcinogenesis. It has been described that APRO proteins also participate in a variety of cellular processes including cell division, DNA repair, and mRNA stability. The biological function of APRO proteins seems to be quite complicated; however, they might be a key modulator of microRNAs (miRNAs) for post-transcriptional regulation. The next generation of therapy would likely contain strategies for modifying the redox background as well as the regulation of ROS in cells and/or for better DNA repair machinery with the APRO proteins via the modulation of miRNA-derived post-transcriptional regulation in a sustainable manner. Given the important function of the gut microbiota in balancing the immune network, carcinogenesis could therefore be prevented by suitable gut microbiota via the roles of APRO proteins. Consequently, probiotics might play a key role in the modulation of gut immune system in keeping healthy and/or preventing cancers.
Aim: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by mono-allelic loss of function variants of transcription factor 4 (TCF4), which plays a key role in early brain developmental and neuronal differentiation. Up to one-half of patients with PTHS will have epilepsy; however, little is known about the characteristic electroencephalogram (EEG) findings in this population. Because there is significant phenotypic overlap between PTHS and other neurodevelopmental disorders such as Angelman syndrome and Rett syndrome, which have characteristic EEG patterns, exploration of a potential EEG signature in patients with PTHS was warranted.
Methods: We conducted a retrospective review of clinical EEGs in patients with PTHS.
Results: In this cohort of patients with PTHS (n = 16), over half had abnormal EEGs; however, no characteristic EEG signature was identified. Further, all patients with epilepsy (5/16) had focal onset seizures with or without secondary generalization, and all five had focal abnormalities on EEG. There was no specific correlation between EEG results and developmental trajectories or age in our patient group, and there was no clear genotype-phenotype correlation.
Conclusion: Although a distinctive EEG signature was not identified, all individuals with epilepsy in our cohort had focal onset seizures with corresponding focal epileptiform discharges or focal slowing on EEG. Future studies are needed to fully elucidate the spectrum of EEG findings in PTHS and explore the pathogenesis of focal seizures in a disorder of neuronal differentiation and development.
Myopia has reached epidemic proportions in the world, especially in East Asia. Pathologic myopia is an extreme type of high myopia that can cause irreversible blindness. Myopic maculopathy is one of the characteristics of pathologic myopia. Nowadays, limited treatments can preserve the visual outcome of these patients. We review the current treatment in practice for myopic maculopathy. Furthermore, based on the current stem cell-based therapy used in degenerative ocular diseases, we discuss a new concept of stem cell therapy for myopic maculopathy.
Maintenance of DNA integrity is crucial for faithful transmission of the genetic code from generation to generation. Our genetic code is constantly under attack from both endogenous and exogenous sources of DNA damage. To ensure genome stability, cells have developed elegant DNA damage repair mechanisms. Defects in DNA damage repair have been linked to several human diseases including promoting oncogenesis, heritable neurodegenerative and neuromuscular diseases caused by unstable DNA repeats, neuropathies and myopathies caused by mutations and rearrangements in mitochondrial DNA, neuropsychiatric disorders, and heritable premature aging syndromes. This review will discuss our current understanding of how these underlying errors in DNA repair contribute to the clinical outcomes of patients who present with these diseases.
Aim: Multiple genes and genetic variants may contribute to racial/ethnic disparities in obesity-associated breast cancer diagnosis and prognosis. Therefore, we evaluate whether racial/ethnic differences in polygenic risk score (PRS) contribute to obesity and inflammatory biomarker in breast cancer patients.
Methods: In a tri-racial/ethnic population of 403 breast cancer patients, 21% African American (AA), 65% Hispanic White (HW), and 14% non-Hispanic White (NHW), we evaluated racial/ethnic differences in obesity PRS, the association between PRS and an inflammatory biomarker C-reactive protein (CRP), and its implication in bariatric surgery eligibility. The obesity PRS was constructed via a weighted risk allele model using 35 obesity-related single nucleotide polymorphisms (SNPs). SAS version 9.3 for Windows (SAS Institute, Cary, NC, USA) was used to perform the logistic regression analysis.
Results: About 74% of our study population were overweight or obese. The mean ± SD of obesity PRS was
Conclusion: In summary, multiple obesity-associated SNPs contribute to racial/ethnic disparities in obesity of breast cancer patients; the obesity PRS has application in identifying breast cancer patients with higher genetic risk for obesity who may benefit from more aggressive weight management, such as bariatric surgery to improve breast cancer clinical outcomes.
Genome-wide association studies (GWAS) have been successful in identifying genetic risk factors for a large number of complex diseases, including age-related macular degeneration (AMD), which is a highly heritable complex disease affecting millions of elderly individuals. However, the progress of elucidating the functional relevance of genetic findings in AMD has been slow, as most risk factors are non-coding, and we have little insight into the causal genes and disease mechanisms. In the last few years, gene expression regulation is emerging as a dominant mechanism through which GWAS risk variants lead to the disease. The purpose of this review is to provide an overview of how transcriptome studies can help in identifying the genes, pathways and therapeutic targets underlying GWAS discoveries in AMD. These approaches help pave the road for mechanistic understanding of GWAS findings and drive translational advances that will lead to improved AMD management and treatment.
Sterol C4-methyloxidase-like (SC4MOL) deficiency is an autosomal recessive condition caused by biallelic pathogenic variants in MSMO1, resulting in the accumulation of 4-monomethyl and 4,4′-dimethyl sterols due to an enzymatic block in the cholesterol synthesis pathway. SC4MOL deficiency was first reported in 2011, with only seven additional cases from five unrelated families described in the literature since. Based on these reports, the most characteristic clinical features include the triad of microcephaly, congenital cataracts, and psoriatic dermatitis, followed by delayed growth and puberty, and neurodevelopmental problems. Herein, we describe an 8-year-old boy who presented with congenital cataracts and developmental delay at age 6 months and was found to have biallelic variants in MSMO1 by trio exome sequencing. Initial total methylsterol levels were elevated but responsive to statin therapy, while total cholesterol levels remained normal throughout. Available clinical and biochemical data suggest this individual could represent the mildest case of SC4MOL deficiency to date.
Aims: Breast and ovarian cancers are frequently associated with mutations in genes involved in DNA double-strand break (DSB) repair by homologous recombination (HR). Risk factors for breast cancer are often linked to estrogen-related pathways. Here, we studied the crosslink between estrogen and the HR pathway.
Methods: We analyzed, using online annotation tolls, the enrichment of candidate estrogen-upregulated genes among DNA repair pathways. We analyzed how estrogen modulates mRNA levels of HR repair (HRR) genes in estrogen-receptor (ER)-positive cells. The cells were deprived of estrogen, and the mRNA levels of HRR genes were determined using real-time polymerase chain reaction, following estrogen addition as well as DNA damage induction. In addition, we examined the effect of estrogen on DNA repair, by immuno-fluorescence analysis, using the DSB marker phospho-histone H2AX, as an indicator for DSB repair. Finally, we performed a clonogenic survival assay to determine the effect of estrogen on cell survival.
Results: We discovered that genes whose mRNA levels are upregulated by estrogen are strongly associated with the HR pathway. We validated that estrogen upregulates mRNA levels of the HRR genes MRE11, RAD50, and PALB2, which have not been previously shown to be regulated by estrogen. Additionally, we revealed that DNA damage induces an upsurge in mRNAs encoding BRCA1, MRE11, RAD50, PALB2, and CtIP, in ER-positive cells deprived of estrogen. Notably, DSB repair was impaired in ER-positive cells deprived of estrogen, compared to cells exposed to the hormone. We also established that ER-positive cells deprived of estrogen are hypersensitive to DSBs.
Conclusion: These results suggest that exposure of ER-positive cells to estrogen triggers the expression of HRR genes, which is required to meet the increased repair demands due to the proliferating effect induced by estrogen. This may explain the higher chances of developing estrogen-dependent cancers due to mutations in HRR genes.
The low-density lipoprotein receptor-related protein 5 gene (LRP5), which encodes a coreceptor within the canonical Wnt signaling pathway, plays a crucial role in bone mass regulation and has been associated with several bone disorders. Autosomal dominant osteopetrosis type I (ADO type I, OMIM 607634) is a rare disease caused by heterozygous, gain-of-function mutations in LRP5. Here we describe a 44-year-old female who presented with thickened calvarium, elevated bone density, torus palatinus, mandibular exostoses, enlarged mandible, and disabling headaches and bone pain. Exome sequencing revealed a previously reported heterozygous missense variant in the LRP5 gene (p.A242T). Post-diagnosis cranial vault volume measurement by computed tomography 3D reconstruction demonstrated decreasing intracranial volume over time. Off-label use of leuprolide acetate was associated with apparent stabilization of skull mineralization. This report documents a severe example of ADO type I and provides anecdotal evidence of the utility of therapy in need of formal evaluation.
Genomic medicine and precision medicine initiatives have taken centre stage in scientific, clinical, as well as health economics and utility research on the global scene for the past decade. It is clear the important role genomic advancement has played in enhancing diagnostic rate, streamlining personalised treatment, and improving efficacy of the overall clinical management of undiagnosed, rare, and common diseases for humankind. The Hong Kong Genome Institute (HKGI) was established in May 2020 within the Food and Health Bureau, Hong Kong Special Administrative Region, to integrate genomic medicine into mainstream healthcare. The main goals of setting up HKGI are to (1) improve the diagnostic rate and future care for individuals affected by undiagnosed diseases and hereditary cancers using whole genome sequencing; (2) advance research in genomic science; (3) nurture talents in genomic medicine; and (4) enhance public genomic literacy and overall engagement through the launching of the Hong Kong Genome Project (HKGP). In this paper, we review the current landscape and specific challenges encountered during the construction of the infrastructure and implementation of the pilot phase of HKGP. Through reviewing what has been achieved and established to date, and the potentials and prospects that have emerged in the process, this paper will provide insights into planning the main phase of HKGP, and considerations for our international counterparts when building similar projects.