A Two-Year Clinical Description of a Patient with a Rare Type of Low-GGT Cholestasis Caused by a Novel Variant of USP53

Here, we report a novel truncating mutation in the ubiquitin-specific peptidase gene (USP53) causing low-γ-GT (GGT) cholestasis. Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. The proband harbored a novel c.1017_1057del (p.(Cys339TrpfsTer7)) mutation in the ubiquitin carboxyl-terminal hydrolase (UCH) domain of USP53; we describe the clinical and laboratory features of the patient with a rare type of low-GGT cholestasis caused by this variant. The clinical presentation was found to be similar to that of phenotypes described in previous studies. However, there was an unusual presence of liver hemangiomas observed in our patient. Thus, our report reinforces the link between USP53 mutations and cholestasis. With this report, we confirm USP53 as the gene for low-GGT cholestasis and describe liver hemangiomas as a possible additional symptom of the phenotype spectrum. The inclusion of USP53 in the OMIM database and liver gene panels can further increase the effectiveness of molecular genetic studies.

Molecular Genetics of Microcephaly Primary Hereditary: An Overview

MicroCephaly Primary Hereditary (MCPH) is a rare congenital neurodevelopmental disorder characterized by a significant reduction of the occipitofrontal head circumference and mild to moderate mental disability. Patients have small brains, though with overall normal architecture; therefore, studying MCPH can reveal not only the pathological mechanisms leading to this condition, but also the mechanisms operating during normal development. MCPH is genetically heterogeneous, with 27 genes listed so far in the Online Mendelian Inheritance in Man (OMIM) database. In this review, we discuss the role of MCPH proteins and delineate the molecular mechanisms and common pathways in which they participate.

Rescuing Lethal Phenotypes Induced by Disruption of Genes in Mice: a Review of Novel Strategies

Approximately 35 % of the mouse genes are indispensable for life, thus, global knock-out (KO) of those genes may result in embryonic or early postnatal lethality due to developmental abnormalities. Several KO mouse lines are valuable human disease models, but viable homozygous mutant mice are frequently required to mirror most symptoms of a human disease. The site-specific gene editing systems, the transcription activator-like effector nucleases (TALENs), Zinc-finger nucleases (ZFNs) and the clustered regularly interspaced short palindrome repeat-associated Cas9 nuclease (CRISPR/Cas9) made the generation of KO mice more efficient than before, but the homozygous lethality is still an undesired side-effect in case of many genes. The literature search was conducted using PubMed and Web of Science databases until June 30th, 2020. The following terms were combined to find relevant studies: “lethality”, “mice”, “knock-out”, “deficient”, “embryonic”, “perinatal”, “rescue”. Additional manual search was also performed to find the related human diseases in the Online Mendelian Inheritance in Man (OMIM) database and to check the citations of the selected studies for rescuing methods. In this review, the possible solutions for rescuing human disease-relevant homozygous KO mice lethal phenotypes were summarized.

Systematic profiling of the effective ingredients and mechanism of Scabiosa comosa and S. tschilliensis against hepatic fibrosis combined with network pharmacology

Scabiosa comosa and S. tschilliensis (SCST) are traditionally used for liver diseases in Mongolian medicine. However, their active ingredients and molecular mechanisms are unknown. The present study employed network pharmacology and experimental verification approaches to decipher the common pharmacological mechanisms of SCST on liver fibrosis, which is the key step in liver diseases. We predicted the targets of all available SCST ingredients with the SWISS and SuperPred servers and clustered the targets related to liver fibrosis from DrugBank, the OMIM database and the literature. We further evaluated the links between the herbal ingredients and pharmacological actions to explore the potential mechanism of action of SCST. We found that the PPARG signalling pathway could be regulated by SCST for liver fibrosis through enrichment analysis. The key targets included 8 co-targets, including HSP90AA1, PPARG, HSP90AB1, STAT1, etc., which play pivotal roles in the pathogenesis of liver fibrosis. Additionally, the top 15 key compounds included flavonoids and phenylpropanoids. Central to the pathogenesis of liver fibrosis is trans-differentiation or activation of hepatic stellate cells (HSCs). Therefore, LX2 cells, an immortalized human HSC line, were studied. Here, a total 37 components were isolated and identified from the inflorescences of SCST, including the new compound tschilliensisin, and the first separated components, β-sitosterol and luteolin, and these compounds were assessed against anti-hepatic fibrosis. An MTT assay and quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analyses demonstrated that the flavonoids of SCST revealed anti-hepatic fibrosis effects via anti-proliferation and increases in the Stat1, Pparg, Hsp90aa1 genes and STAT1 and PPARG proteins in LX-2 cells. In conclusion, these results indicate that SCST has multi-targeted and multi-component synergistic anti-hepatic fibrosis effects.

Genetics in Ophthalmology

На сегодняшний день в базе данных Online Mendelian Inheritance in Man (OMIM) описано более 6613 заболеваний и фенотипов, 4241 имеют доказанную генетическую основу, не менее 45% вкючают офтальмологические проявления. В статье приведен ряд клинический примеров пациентов с офтальмологическими симптомами различных генетических заболеваний (алкаптонурия, болезнь Штаргардта, синдром микроцефалии с или без хориоретинопатии; астроцитарная гамартома) с целью демонстрации эффективного клинико-диагностического скрининга генетической патологии у пациентов. So far, the Online Mendelian Inheritance in Man (OMIM) database describes more than 6613 diseases and phenotypes, 4241 have a proven genetic basis, 45% of which are combined with ophthalmological manifestations. The article provides a number of clinical examples of patients with ophthalmological manifestations of various genetic diseases (alcaptonuria, Stadgart ‘s disease, microcephaly syndrome with or without choriretinopathy; Astrocytic gamartoma) to demonstrate effective clinical-diagnostic screening of genetic pathology in patients.

Exploring the Mechanisms of Lian Hua Qing Wen Capsule against COVID-19 by Network Pharmacology and Molecular Docking Approach

Background The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) disease has led to a wide-spread global pandemic. There is no specific antiviral drug proven effective for the treatment of patients with COVID-19 at present. Combination of western and traditional Chinese medicine (TCM) is recommended, and Lian Hua Qing Wen (LHQW) capsule is a basic prescription and widely used to treat COVID-19 in China. However, the mechanisms of LHQW capsule treating COVID-19 are not clear. The aim of the study is to explore the mechanisms of LHQW capsule treating COVID-19 based on network pharmacy and molecular docking approach. Methods The active compounds and targets of LHQW capsule were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). COVID-19 related target genes were obtained from GeneCards database and OMIM database. Protein–protein interaction (PPI) networks of LHQW capsule targets and COVID-19-related genes were visualized and merged to identify the candidate targets for LHQW capsule treating COVID-19. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed. The hub genes involved in the gene-related pathways were screened and their corresponding compounds were used for in vitro validation of molecular docking predictions.Results A total of 185 active compounds of LHQW capsule were screened out, and 263 targets were predicted. Third hundred and fifty-two COVID-19 related target genes were obtained from GeneCards database and OMIM database. GO functional enrichment analysis showed that the biological processes of LHQW capsule treating COVID-19 were closely linked with the regulation of inflammation, immunity, cytokines production, vascular permeability, oxidative stress and apoptosis. KEGG enrichment analysis revealed that the pathways of LHQW capsule treating COVID-19 were significantly enriched in AGE−RAGE signaling pathway in diabetic complications, Kaposi sarcoma−associated herpesvirus infection, TNF, IL−17, and Toll−like receptor (TLR) signaling pathway. The hub targets genes in the gene-related pathways analysis of LHQW capsule treating COVID-19 included MAPK1, MAPK3, RELA, IL-6 and CASP8, which closely associated with inflammation, cytokines storm and apoptosis. Finally, molecular docking showed that top 5 compounds of LHQW capsule also had good binding activities to the important targets in COVID-19.Conclusions The mechanisms of LHQW capsule treating COVID-19 may involve in inhibiting inflammatory response, cytokine storm and virus infection, and regulating immune reactions, apoptosis and endothelial barrier.

WikiMedMap: Expanding the Phenotyping Mapping Toolbox Using Wikipedia

Researchers utilizing phenotypic data from diverse sources require matching of phenotypes to standard clinical vocabularies. Mapping phenotypes to vocabulary can be difficult, as existing tools are often incomplete, can be difficult to access, and can be cumbersome to use, especially for non-experts. We created WikiMedMap as a simple tool that leverages Wikipedia and maps phenotype strings to standard clinical vocabularies. We assessed WikiMedMap by mapping phenotype strings from questionnaires in the UK Biobank and from Mendelian diseases in Online Mendelian Inheritance in Man (OMIM) database to eight vocabularies: International Classification of Diseases, Ninth Revision (ICD-9), ICD-10, ICD-O, Medical Subject Headings (MeSH), OMIM, Disease Database, and MedlinePlus. WikiMedMap outperformed conventional mapping tools in finding potential matches for phenotype strings. We envision WikiMedMap as a technique that complements existing and established tools to map strings to clinical vocabularies that usually do not coexist in one source.

A Rare Case of Concomitant Deletions in 15q11.2 and 19p13.3

A female individual with concomitant deletions in 15q11.2 and 19p13.3 is reported. She presents facial dysmorphisms, motor delay, learning difficulties, and mild behavioral impairment. After chromosomal microarray analysis, the final karyotype was established as 46,XX.arr[GRCh37] 15q11.2 (22770421_23282798)×1,19p13.3(3793904_4816330)×1. The deletion in 15q11.2 is 507 kb in size involving 7 non-imprinted genes, 4 of which are registered in the OMIM database and are implicated in neuropsychiatric or neurodevelopmental disorders. The deletion in 19p13.3 is 1,022 kb in size and encompasses 47 genes, most of which do not have a well-known function. The genotype-phenotype correlation is discussed, and most of the features could be related to the 19p13.3 deletion, except for velopharyngeal insufficiency. Other genes encompassed in the deleted region, as well as unrecognized epistatic factors could also be involved. Nevertheless, the two-hit model related to the 15q11.2 deletion would be an important hypothesis to be considered.

Microdeletion 15q26.2qter and Microduplication 18q23 in a Patient with Prader-Willi-Like Syndrome: Clinical Findings

The small interstitial deletion in the long arm of chromosome 15 causing Prader-Willi/Angelman syndrome is well known, whereas cases that report terminal deletions in 15q in association with the Prader-Willi-like phenotype are very rare. By using GTG-banding analysis, metaphase FISH, MLPA analysis, and genome-wide array CGH, we detected an unbalanced translocation involving a microdeletion of the distal part of 15q and a microduplication of the distal part of 18q. The unbalanced translocation was found in a boy that was referred with clinical suspicion of Prader-Willi syndrome. In the 15q-deleted region, 23 genes have been identified, and 13 of them are included in the OMIM database. Among these, the deleted IGFR1, MEF2A, CHSY1, and TM2D3 genes could contribute to the patient's phenotype. Seven genes are included in the duplicated chromosome segment 18q, but only one (CTDP1) is present in the OMIM database. We suggest that the deleted chromosome segment 15q26.2qter may be responsible for the phenotype of our case and may also be a candidate locus of Prader-Willi-like syndrome.