Related Genetic Diseases Research Articles

Identification of novel RIPK4 variants in a Chinese patient with Arthrogryposis Multiplex Congenita (AMC)

BackgroundArthrogryposis multiplex congenita (AMC) is a congenital disorder characterized by multiple joint involvement, primarily affecting limb mobility and leading to various tissue contractures. Variations in the RIPK4 gene may impact connective tissues, thereby resulting in a spectrum of malformations. This study aimed to identify the genetic etiologies of AMC patients and provide genetic testing information for further diagnosis and treatment of AMC.MethodsWe recruited a Chinese female patient with hand-related AMC and her family members. Whole-exome sequencing (WES) was employed to determine the genetic etiologies of the patient’s disease. The pathogenic mechanisms of the identified variations were analyzed using protein tolerance profiling and modeling.ResultsWe identified two novel RIPK4 variants (c.1354G > A, p.E452K; c.1558A > T, p.T520S). Pathogenicity studies indicated that the c.1354G > A, p.E452K variant changed the charge from negative to positive and altered the chemical properties from acidic to alkaline, potentially significantly affecting protein function.ConclusionsWe reported the discovery of two novel RIPK4 variants (c.1354G > A, p.E452K; c.1558A > T, p.T520S) in a Chinese AMC female patient’s family. Our study enhances the genetic repository for AMC and highlights the pathogenicity of RIPK4 variants, underscoring the significance of comprehensive management for genetic-related diseases, particularly the critical roles of prenatal diagnosis and genetic counseling.Trial registrationThe research protocol received approval from the Ethics Review Committee of Xiangya Hospital of Central South University in China (approval number: 202103427), registered in March 2021, with all participants providing duly signed informed consent forms.

Studies on the association of genes with language disorders in the post-genomic era

Since genetic research entered the post-genomic era, the high heritability of language disorders has been confirmed. A variety of genetic-related diseases may cause various types of language disorders in children and/or adults. This article has summarized language disorders and their underlying mechanisms by searching the Web of Science database over the last decade, and combed the genetic researches for dyslexia, frontotemporal degeneration, specific language disorder, childhood speech apraxia and other single diseases that are strongly associated with the language disorders. It also provided a discussion over the co-occurrence of multiple diseases, with an aim to revealing the genetic association and/or pathogenetic mechanism in order to provide inspiration for the prevention, diagnosis, and treatment of language disorders.

Understanding cultural values, norms and beliefs that may impact participation in genome-editing related research: Perspectives of local communities in Botswana.

Gene-editing research is a complex science and foreign in most communities including Botswana. Adopting a qualitative deliberative framework with 109 participants from 7 selected ethnic communities in Botswana, we explored the perceptions of local communities on cultural values, norms, and beliefs that may motivate or deter likely participation in the use of gene-editing related research. What emerged as the ethnic community's motivators for research participation include the potential for gene-editing technologies to promote access to individualized medications, and the possibility of protecting family members from genetic related diseases. Deterrents for research participation include cultural values such as implications of lineage for chieftainship, trust, fear or anxiety, uncertainty, and sensitivity on the use of gene-editing. Findings of our study have implications for continuous engagement with local communities to explore potential ways of addressing cultural sensitivities that can further deter their participation in future gene-editing related research.

Advances in Anti-obesity Pharmacotherapy: Current Treatments, Emerging Therapies, and Challenges.

Obesity is a major public health concern linked to health risks such as hypertension, hyperlipidemia, type 2 diabetes mellitus (T2DM), stroke, metabolic syndrome, asthma, and cancer. It is among the leading causes of morbidity and mortality worldwide caused by an unhealthy diet and lack of physical activity, but genetic or hormonal factors may also contribute. Over a third of adults in the United States are obese. Pharmacological agents have been designed to reduce weight gain caused by excessive calorie intake and low physical activity. They work by inhibiting the absorption of dietary fat or stimulating the secretion of satiety hormones. These drugs include lipase inhibitors and glucagon-like peptide1 (GLP-1) receptor agonists. However, the current weight-loss strategies do not effectively treat genetic-related diseases, such as generalized lipodystrophy, Bardet-Biedl syndrome, and proopiomelanocortin (POMC) deficiency. Emerging therapies for these gene mutations have been developed targeting leptin and melanocortin-4 receptors (MC4Rs), restoring the normal function of leptin or melanocortin-4 receptors regulating energy balance and appetite. Leptin analogs and MC4R agonists are novel therapies that target genetic or hormonal causes of obesity. This article provides a comprehensive review of anti-obesity medications (AOMs). In this review, we discuss the clinical trials, efficacy, United States FDA-approved indication, contraindications, and serious side effects of different classes of drugs, including lipase inhibitors, GLP-1 agonists, leptin analogs, and MC4R agonists.

Benzo[a]pyrene-induced up-regulation of circ_0003552 via ALKBH5-mediated m6A modification promotes DNA damage in human bronchial epithelial cells

Benzo [a]pyrene (B [a]P) is a widespread environmental chemical pollutant that has been linked to the development of various diseases. However, the specific mechanism of action remains unclear. In this study, human bronchial epithelial 16HBE and BEAS-2B cells were exposed to B [a]P at 0–32 μM to assess the DNA-damaging effects. B [a]P exposure resulted in elevated expression of γ-H2AX, a marker of DNA damage. The m6A RNA methylation assay showed that B [a]P exposure increased the extent of m6A modification and the demethylase ALKBH5 played an integral role in this process. Moreover, the results of the comet assay and Western blot analysis showed an increase in m6A modification mediated by ALKBH5 that promoted DNA damage. Furthermore, the participation of a novel circular RNA, circ_0003552, was assessed by high-throughput sequencing under the condition of high m6A modification induced by B [a]P exposure. In subsequent functional studies, an interference/overexpression system was created to confirm that circ_0003552 participated in regulation of DNA damage. Mechanistically, circ_0003552 had an m6A binding site that could regulate its generation. This study is the first to report that B [a]P upregulated circ_0003552 through m6A modification, thereby promoting DNA damage. These findings revealed that epigenetics played a key role in environmental carcinogen-induced DNA damage, and the quantitative changes it brought might provide an early biomarker for future medical studies of genetic-related diseases and a new platform for investigations of the interaction between epigenetics and genetics.

A self-supply crRNA-mediated CRISPR/Cas12a-driven controlled-release homogeneous biosensor for ultrasensitive detection of microRNA

The abnormal expression of microRNAs (miRNAs) will lead to the occurrence of cancer and serious genetic related diseases. In this work, a novel self-supply crRNA-mediated CRISPR/Cas12a-driven controlled-release homogeneous biosensor was developed for ultra-sensitivity detection of miRNA-155, using single stranded DNA1 (ssDNA1, S1) as a bio-gate and UiO-66-NH2 as a nanocontainer. Initially, the exponential amplification reaction (EXPAR) was designed to transform and amplify the target recognition event into the T7 promoter, which could function as a trigger for transcription amplification to generate a large number of crRNA. The abundant crRNA formed a ternary complex with Cas12a and activator, and the trans-cleavage activity of the CRISPR/Cas12a was activated. Then the ssDNA2 completely complementary to ssDNA1 was cleaved, resulting in inability to form double-stranded DNA (dsDNA), which made ssDNA1 inseparable from UiO-66-NH2. Eventually, the stored methylene blue (MB) signal cannot be released from UiO-66-NH2. On the contrary, the ssDNA1 bio-gate was opened, and MB signal molecules escaped from the container, producing an obvious current signal. Through triple signal amplification and precise control and release system, the prepared biosensor could realize an ultralow detection limit of miRNA-155 as low as 31.6 aM. More importantly, the proposed strategy showed excellent sensitivity and specificity in complex serum environments and tumor cell lysates, providing a new approach to develop a robust tool for disease diagnosis.

Acute brain injury after pulmonary nodule surgery with ornithine transcarboxylase deficiency: A case report and literature review

Ornithine Trans Carboxylase Deficiency (OTCD) is a rare congenital genetic related disease.

Focal segmental glomerular sclerosis can be effectively treated using an intensive B-cell depletion therapy.

Focal segmental glomerular sclerosis (FSGS) is a histologic lesion rather than a specific disease entity and represents a cluster of different conditions affecting both children and adults that includes primary, secondary and genetically mediated forms. These forms can be distinguished by electron microscopy and genetic assessment and show different responsiveness to steroids and immunosuppressants. Despite some promising effects of rituximab in nephrotic syndrome in children, the results in adults with FSGS are disappointing. Our group previously explored the effectiveness of rituximab in eight adult patients with unselected forms of FSGS and achieved a consistent reduction in proteinuria in one case. Following this experience, we developed an alternative therapeutic option intended to enhance the potential of rituximab with the support of other synergic drugs. We herein report the results of this therapeutic protocol (six administrations of rituximab plus two of intravenous cyclophosphamide plus glucocorticoids) in seven prospectively enrolled patients with extensive podocyte effacement and recurrent relapses or steroid dependence. Patients had a median baseline serum creatinine level of 2.2mg/dl (range 1-4.7) that decreased to 1.1mg/dl (range 0.9-2.2) and 1.1mg/dl (range 0.75-2.21) after 3 and 6months, respectively, and remained unchanged at 12months. Three of five patients with renal failure turned to normal function while the other two patients maintained a stable impairment after 18 and 52months. The median proteinuria decreased from 6.1g/24h to 3.5, 3.5 and 1.9g/24h at 3, 6 and 12months, respectively. Specifically, five of seven patients had a partial response at 12months and became non-nephrotic. One of them had a complete response at 18months and was still in complete remission at the last follow-up visit at 36months. Proteinuria persisted unchanged in two of seven patients with a genetic-related disease. No serious late adverse events were observed. Our results show that intensive B-cell depletion therapy is able to reverse the nephrotic syndrome of steroid-dependent or frequently relapsing adult patients with putatively idiopathic FSGS (i.e. with extensive podocyte effacement).

DNA damage and repair in the hematopoietic system.

Although hematopoietic stem cells (HSCs) in the bone marrow are in a state of quiescence, they harbor the self-renewal capacity and the pluripotency to differentiate into mature blood cells when needed, which is key to maintain hematopoietic homeostasis. Importantly, HSCs are characterized by their long lifespan ( e. g., up to 60 months for mice), display characteristics of aging, and are vulnerable to various endogenous and exogenous genotoxic stresses. Generally, DNA damage in HSCs is endogenous, which is typically induced by reactive oxygen species (ROS), aldehydes, and replication stress. Mammalian cells have evolved a complex and efficient DNA repair system to cope with various DNA lesions to maintain genomic stability. The repair machinery for DNA damage in HSCs has its own characteristics. For instance, the Fanconi anemia (FA)/BRCA pathway is particularly important for the hematopoietic system, as it can limit the damage caused by DNA inter-strand crosslinks, oxidative stress, and replication stress to HSCs to prevent FA occurrence. In addition, HSCs prefer to utilize the classical non-homologous end-joining pathway, which is essential for the V(D)J rearrangement in developing lymphocytes and is involved in double-strand break repair to maintain genomic stability in the long-term quiescent state. In contrast, the base excision repair pathway is less involved in the hematopoietic system. In this review, we summarize the impact of various types of DNA damage on HSC function and review our knowledge of the corresponding repair mechanisms and related human genetic diseases.

Can we understand the mechanisms of tumor formation by analyzing dynamics of cancer initiation?

Cancer is a collection of related genetic diseases exhibiting uncontrolled cell growth that interferes with normal functioning of human organisms. It results from accumulation of unfavorable mutations in tissues. While the biochemical picture of how cancer appears is known, the molecular mechanisms of tumor formation remain not fully understood despite tremendous efforts of researchers in multiple fields. New approaches for investigating cancer are constantly sought. In this paper, we discuss a powerful method of clarifying better a more microscopic picture of cancer by analyzing the dynamics of tumor formation. Using physics- and chemistry-inspired discrete-state stochastic description of cancer initiation, it is shown how the mechanisms of tumor formation can be uncovered. This approach is suggested as a powerful new physical-chemical tool for a better understanding of complex processes associated with cancer.

Experience and lessons on guiding and governing clinical applications of chromosome microarray analysis in the United States

Chromosome microarray analysis (CMA) has become the first-tier testing for chromosomal abnormalities and copy number variations (CNV). This review described the clinical validation of CMA, the development and updating of technical standards and guidelines and their diagnostic impacts. The main focuses were on the development and updating of expert consensus, practice resources, and a series of technical standards and guidelines through systematic review of case series with CMA application in the literature. Expert consensus and practice resource supported the use of CMA as the first-tier testing for detecting chromosomal abnormalities and CNV in developmental and intellectual disabilities, multiple congenital anomalies and autism. The standards and guidelines have been applied to pre- and postnatal testing for constitutional CNV and tumor testing for acquired CNV. CMA has significantly improved the diagnostic yields but still needs to overcome its technical limitations and face challenges of new technologies. Guiding and governing CMA through expert consensus, practice resource, standards and guidelines in the United States has provided effective and safe diagnostic services to patients and their families, reliable diagnosis on related genetic diseases for clinical database and basic research, and references for clinical translation of new technologies.

Demethyltransferase AlkBH1 substrate diversity and relationship to human diseases.

AlkBH1 is a member of the AlkB superfamily which are kinds of Fe (II) and α-ketoglutarate (α-KG)-dependent dioxygenases. At present, only demethyltransferases FTO and AlkBH5 have relatively clear substrate studies among these members, the types and mechanisms of substrates catalysis of other members are not clear, especially the demethyltransferase AlkBH1. AlkBH1, as a demethylase, has important functions of reversing DNA methylation and repairing DNA damage. And it has become a promising target for the treatment of many cancers, the regulation of neurological and genetic related diseases. Many scholars have made important discoveries in the diversity of AlkBH1 substrates, but there is no comprehensive summary, which affects the design inhibitor target of AlkBH1. Herein, We are absorbed in the latest progress in the study of AlkBH1 substrate diversity and its relationship with human diseases. Besides, we also discuss future research directions and suggest other studies to reveal the specific catalytic effect of AlkBH1 on cancer substrates.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Probably Caused by DSG2 p.Val149Ile Mutation as Genetic Background When Carrying with Heterozygous PRRT2 p.Arg217ProfsTer8 Mutation: A Case Report

BackgroundARVC is a rare genetic-related disease characterized by fibrous fat replacement in the ventricular myocardium, caused by mutations in genes encoding for the desmosomal proteins, such as the desmoglein-2 gene (DSG2). It is reported in the literature that other genetic factors may play a role in disease penetrance. Herein, we report a Chinese proband with ARVC, which was probably caused by DSG2 p.Val149Ile mutation as genetic background when carrying heterozygous PRRT2 p.Arg217ProfsTer8 mutation.Case PresentationA 17-year-old male with a history of paroxysmal kinesigenic dyskinesia (PKD) presented to the hospital for syncope induced by ventricular tachycardia. According to relevant clinical data and the diagnostic criteria of ARVC, a precise positive diagnosis of ARVC was finally made. Gene testing revealed that the patient carried a DSG2 heterozygous missense mutation (NM_001943: exon5: c.445G>A, p.Val149Ile) as well as frameshift mutation of PRRT2 (NM_001256442: exon2: p. Arg217Profs Ter8).ConclusionThis is the first time to report a Chinese proband with ARVC and a history of PKD carrying both DSG2 p. val149ile mutation and PRRT2 p. Arg217ProfsTer8 mutation, which can provide a new direction for gene screening of patients with ARVC and further supplements for its diagnostic criteria.

Consanguinity, awareness, and genetic disorders among female university students in Riyadh, Saudi Arabia

Background: There is a high rate of consanguinity and related genetic diseases in the general population of Saudi Arabia. Studies have been conducted to address the level of awareness about consanguineous marriages (CM); however, targeted young female studies are still limited. The association between consanguinity and socio-demographic information and the prevalence of consanguinity among educated female university students of Princess Nourah Bint Abdulrahman University (PNU), Riyadh, Saudi Arabia, is being addressed in the present study. Methodology: A cross-sectional web-based questionnaire study was conducted randomly among PNU students from October 3 to November 2, 2019. Multivariable data analysis was conducted, and an odds ratio was calculated to identify factors associated with CM and health outcomes. Results: Among the 637 students who completed the questionnaire, consanguinity was significantly higher among participants than their parents, as 37.88% of the 293 married participants had CM. A strong correlation was found between parents and their daughters; consanguinity was highest (52.27%) in the daughters of parents who were in consanguineous marriages themselves. The general high level (91.51%) of awareness about CM’s consequences and their link to genetic diseases was found. However, a lack of knowledge about the type of diseases was noted among participants. Diabetes and blood diseases were the most common diseases in different CM groups. Conclusion: Despite the high levels of awareness, more targeted awareness campaigns are needed, especially among the younger generation.

Expanding our understanding of fetal genetic diseases: the beginning of in utero precision medicine.

As genetic technologies evolve, our understanding of the causes of fetal structural anomalies and related fetal genetic diseases will expand. This ability will no longer mean that with the discovery of a severe fetal anomaly the patient must decide to either terminate the pregnancy or risk having a child with potentially severe and lifelong difficulties, the extent of which can only be reliably elucidated postnatally. However, implementation of in-utero genomic testing now allows "precision fetal medicine" in which specific fetal diagnosis and prognosis are available.

Effects of HTR1B 3\u2032 region polymorphisms and functional regions on gene expression regulation

BackgroundThe HTR1B gene encodes the 5-hydroxytryptamine (5-HT1B) receptor, which is involved in a variety of brain activities and mental disorders. The regulatory effects of non-coding regions on genomic DNA are one of many reasons for the cause of genetic-related diseases. Post-transcriptional regulation that depends on the function of 3′ regulatory regions plays a particularly important role. This study investigated the effects, on reporter gene expression, of several haplotypes of the HTR1B gene (rs6297, rs3827804, rs140792648, rs9361234, rs76194807, rs58138557, and rs13212041) and truncated fragments in order to analyze the function of the 3′ region of HTR1B.ResultsWe found that the haplotype, A-G-Del-C-T-Ins-A, enhanced the expression level compared to the main haplotype; A-G-Del-C-G-Ins-A; G-G-Del-C-G-Ins-G decreased the expression level. Two alleles, rs76194807T and rs6297G, exhibited different relative luciferase intensities compared to their counterparts at each locus. We also found that + 2440 ~ + 2769 bp and + 1953 ~ + 2311 bp regions both had negative effects on gene expression.ConclusionsThe 3′ region of HTR1B has a regulatory effect on gene expression, which is likely closely associated with the interpretation of HTR1B-related disorders. In addition, the HTR1B 3′ region includes several effector binding sites that induce an inhibitory effect on gene expression.

Targeting Myeloid-Derived Suppressor Cells Is a Novel Strategy for Anti-Psoriasis Therapy.

Psoriasis is a common immune-mediated, chronic inflammatory genetic-related disease that affects patients' quality of life. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of progenitor and immature myeloid cells which are expanded in psoriatic skin lesions and peripheral blood. However, the role of MDSCs in the pathogenesis of psoriasis remains unclear. Here, we confirmed that the accumulation of human MDSCs is remarkably increased in skin lesions of psoriasis patients by flow cytometry. Depleting MDSCs by Gemcitabine significantly suppresses IMQ-induced psoriatic inflammation and epidermal thickening as well as Th17 and Treg cell accumulation. Moreover, through the RNA-Seq technique, we validated some differentially expressed genes on CD4+ T-cells of IMQ-induced-MDSC-depleted mice such as IL-21 and Timd2, which are involved in Th17-cell differentiation or T-cell activation. Interestingly, neutralizing IL-21R by antibody reduces IMQ-induced epidermal thickening through downregulating the infiltration of MDSCs and Th17 cells. Our data suggest that targeting myeloid-derived suppressor cells is a novel strategy for antipsoriasis therapy. IL-21 may be a potential therapeutic target in psoriasis.

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases.

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease

Mutations in the X-linked gene IQSEC2 are associated with multiple cases of epilepsy, epileptic encephalopathy, intellectual disability and autism spectrum disorder, the mechanistic understanding and successful treatment of which remain a significant challenge in IQSEC2 and related neurodevelopmental genetic diseases. To investigate disease etiology, we studied behaviors and synaptic function in IQSEC2 deficient mice. Hemizygous Iqsec2 null males exhibit growth deficits, hyperambulation and hyperanxiety phenotypes. Adult hemizygotes experience lethal spontaneous seizures, but paradoxically have a significantly increased threshold to electrically induced limbic seizures and relative resistance to chemically induced seizures. Although there are no gross defects in brain morphology, hemizygotes exhibit stark hippocampal reactive astrogliosis. Electrophysiological recordings of hippocampal neurons reveal increased excitatory drive specifically onto interneurons, and significant alterations in intrinsic electrical properties specific to the interneuron population. As they age, hemizygotes also develop an increased abundance of parvalbumin-positive interneurons in the hippocampus, neurons in which IQSEC2 is expressed in addition to the excitatory neurons. These findings point to a novel role of IQSEC2 in hippocampal interneuron synaptic function and development with implications for a class of intractable neurodevelopmental diseases.

What Motivates Individuals to Get Obesity Related Direct-To-Consumer Genetic Tests? A Reasoned Action Approach

ABSTRACTBackground: Research suggest that genetic testing and its application (personalized medicine/precision medicine) has great potential to help public health professionals deliver proper health promotion and education to target populations who have high predispositions for certain genetic-related diseases. Purpose: The purpose of this study was to use the Reasoned Action Approach (RAA) to investigate factors that influence behavioral intentions for obtaining an Obesity Related Direct-to-Consumer Genetic Tests (ODTCGT). Methods: This study utilized a cross-sectional design. Data were collected by an online questionnaire and administered to a sample attending a large public Southwestern university (n = 288). Results: Perceived norms, attitudes, and perceived behavioral control predicted a significant amount of the variance of behavioral intentions (adjusted R2 = 0.642). An independent group t-test showed that those who had prior knowledge of the obesity gene, and genetic testing, had significantly higher behavioral intentions, and behavioral antecedents. Discussion: Results from this study show that the RAA is a valid and robust model for investigating one’s behavioral intention of obtaining ODTCGT, and attitudes, perceived norms, and PBC.Translation to Health Education Practice: Findings from this study suggest that to motivate young adults, public health educators should create strategies to change their perceived norms (stemming from descriptive norms).A AJHE Self-Study quiz is online for this article via the SHAPE America Online Institute (SAOI) http://portal.shapeamerica.org/trn-Webinars