Characterisation of the novel HLA-C*01:273 allele, first identified in a Brazilian individual.

The novel HLA-C*01:273 allele, first described in a potential bone marrow donor from Brazil.

Identification of the novel HLA-A*30:221 allele by next-generation sequencing.

The novel HLA-A*30:221 allele differs from HLA-A*30:01:01:01 by one nucleotide substitution in Exon 7.

Characterisation of the novel HLA-B*46:96 allele by next-generation sequencing.

HLA-B*46:96 differs from HLA-B*46:01:01:01 by a single nucleotide substitution at position 479 C>T.

The novel HLA-C*04:01:01:182 allele identified in a candidate bone marrow donor by next-generation sequencing.

HLA-C*04:01:01:182 differs from the HLA-C*04:01:01:06 allele by one nucleotide substitution in the 5'UTR.

The novel HLA-DRB1 allele, HLA-DRB1*09:54 was identified in a Chinese individual.

HLA-DRB1*09:54 shows a substitution G to A at position 449 when compared with HLA-DRB1*09:01:02:01.

The novel HLA-C*14:02:01:31 allele identified in a candidate bone marrow donor by next-generation sequencing.

Characterisation of the novel HLA-C*14:02:01:31 allele in a 21-year-old Greek bone marrow donor.

The novel HLA-A allele, HLA-A*03:478, identified in a Korean individual.

One nucleotide substitution in codon 320 of A*03:01:01:01 results in the novel allele, HLA-A*03:478.

Meet the authors: Mei-Sheng Xiao, Arun Prasath Damodaran, and Thomas Gonatopoulos-Pournatzis.

We talk to corresponding author Thomas Gonatopoulos-Pournatzis and co-first authors Arun Prasath Damodaran and Mei-Sheng Xiao about their paper "Genome-scale exon perturbation screens uncover exons critical for cell fitness" (in this issue of Molecular Cell) and get insights into their findings, career trajectories, and future directions in the pre-mRNA processing field.

Efficacy and tolerability of capmatinib in a very elderly patient with metastatic NSCLC harboring a MET exon 14 mutation.

We report the case of an 87-year-old female patient who was diagnosed with metastatic non-small-cell lung cancer harboring MET exon 14 skipping mutation (MET ex14) and PD-L1 expression of 60%. A first-line treatment with atezolizumab was started with primary resistance. Then, a second-line treatment with capmatinib, a selective type Ib MET tyrosine kinase inhibitor, was started, achieving a partial response. The patient is still alive and on treatment with capmatinib 300 mg twice daily after 20 months, with a good tolerability and no evidence of disease progression.In summary, our patient experienced a long-lasting response (>18 months) with capmatinib as second-line treatment. Further analyses evaluating the efficacy and tolerability of MET tyrosine kinase inhibitors are warranted, especially in the elderly, a non-small-cell lung cancer population whose tumors could more frequently harbor MET ex14 mutation.

[Box: see text].

SimSpliceEvol2: alternative splicing-aware simulation of biological sequence evolution and transcript phylogenies.

BACKGROUND: SimSpliceEvol is a tool for simulating the evolution of eukaryotic gene sequences that integrates exon-intron structure evolution as well as the evolution of the sets of transcripts produced from genes. It takes a guide gene tree as input and generates a gene sequence with its transcripts for each node of the tree, from the root to the leaves. However, the sets of transcripts simulated at different nodes of the guide gene tree lack evolutionary connections. Consequently, SimSpliceEvol is not suitable for evaluating methods for transcript phylogeny inference or gene phylogeny inference that rely on transcript conservation. RESULTS: Here, we introduce SimSpliceEvol2, which, compared to the first version, incorporates an explicit model of transcript evolution for simulating alternative transcripts along the branches of a guide gene tree, as well as the transcript phylogenies inferred. We offer a comprehensive software with a graphical user interface and an updated version of the web server, ensuring easy and user-friendly access to the tool. CONCLUSION: SimSpliceEvol2 generates synthetic datasets that are useful for evaluating methods and tools for spliced RNA sequence analysis, such as spliced alignment methods, methods for identifying conserved transcripts, and transcript phylogeny reconstruction methods. The web server is accessible at https://simspliceevol.cobius.usherbrooke.ca , where you can also download the standalone software. Comprehensive documentation for the software is available at the same address. For developers interested in the source code, which requires the installation of all prerequisites to run, it is provided at  https://github.com/UdeS-CoBIUS/SimSpliceEvol .

Identification of eight new HLA class I alleles by next-generation sequencing.

Eight novel HLA class I alleles detected by next-generation sequencing.

A novel splice-altering TNC variant (c.5247A > T, p.Gly1749Gly) in an Chinese family with autosomal dominant non-syndromic hearing loss.

BACKGROUND: This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene. METHODS: A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis. RESULTS: The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon-intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19. CONCLUSION: This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

[Clinical and genetic characteristics of a case of primary ciliary dyskinesia caused by new frameshift mutation of the DNAH5 gene].

OBJECTIVE: To investigate the clinical and genetic characteristics of a case of primary ciliary dyskinesia (PCD). METHODS: We collected the clinical data on a case of PCD treated in the Department of Reproductive Medicine of Linyi People's Hospital in July 2020, detected the genes of the patient by whole-exome sequencing (WES), verified the candidate mutations by Sanger sequencing, and predicted the protein structure of the mutant gene by SWISS-MODEL. RESULTS: The proband was found with the clinical phenotypes of chronic rhinitis, bronchiectasis, visceral transposition and male infertility. WES revealed a homozygous frameshift variation of c.12890dup (p.N4297Kfs*13) in exon 74 of the DNAH5 gene, which led to the premature termination of polypeptide chain synthesis and affected the gene function. SWISS-MODEL prediction showed that some of the amino acid residues were deleted after mutation, resulting in a 3D conformational change of the protein. This variation was not recorded in the ClinVar, gnomAD and OMIM databases and, according to the relevant guidelines of the American College of Genetics and Genomics, was classified as a pathogenic variation (PVS1+PM2_P+PM3_P). CONCLUSION: The homozygous variation of the DNAH5 gene c.12890dup (p.N4297Kfs*13) may be the cause of the clinical phenotype of this case of PCD, and the above findings have enriched the variation spectrum of the DNAH5 gene.

Identification of the novel allele HLA-A*02:1144 in a Chinese platelet donor.

The novel HLA-A*02:1144 allele differs from HLA-A*02:03:01:01 by 3 nucleotides in exon 7.

HLA-B*51:197: A composite product of interlocus recombination of B*51:01:01:01 and C*01:02:01:01.

The HLA-B*51:197 allele is generated from the interlocus recombination of both HLA-B*51:01:01:01 and HLA-C*01:02:01:01 alleles.

Identification of the novel HLA-A*11:01:117 allele by next-generation sequencing.

HLA-A*11:01:117 differs from HLA-A*11:01:01:01 by a single nucleotide substitution at position 780 A>G.

Identification of the new allele HLA-A*24:632 in a Greek individual using next generation sequencing.

The HLA-Α*24:632 allele differs from HLA-A*24:02:01:01 by a single nucleotide substitution in exon 2.

Molecular analyses of MEFV gene mutation variants in Turkish population.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease primarily affecting individuals of Turkish, Armenian, Arab, and non-Ashkenazi Jewish descent, caused by mutations in the MEFV gene. The aim of this study was to review the common genotype distributions of MEFV variants and mutations in the Turkish population and evaluate rare mutations. METHODS AND RESULTS: The study included 2984 patients who applied to Ankara University Ibni Sina Hospital Immunology Laboratory with clinical suspicion of FMF between 2004 and 2014. The data of patients from different regions of the country who were followed up in the immunology-rheumatology clinic with clinical suspicion and presumptive diagnosis of FMF were evaluated retrospectively. Patients were tested for all mutations in Exon 2 and Exon 10, including M694V, M680I, M694I, V726A, E148Q and R202Q. There were 2504 patients with FMF variant. According to genotyping, R202Q (n = 1567, 39.2%) was the most common mutation. The most common co-variant was the R202Q/M694V genotype (n = 507, 16.98%). Allele frequencies for MEFV mutations were as follows: R202Q (n = 1567, 39.2%), M694V (n = 1004, 25.1%), E148Q (n = 463, 11.5%), M680I (n = 354, 8.8%), V726A (n = 319, 7.9%), A744S (n = 51, 1.2%), R761H (N = 41, 1.0%), P706P (N = 25, 0.6%), E167D (N = 23, 0.5%), M694I (N = 23, 0.5%), and K695R (N = 20, 0.5%). CONCLUSION: This research revealed the prevalence of both common and rare MEFV gene mutations in Turkish FMF patients in various age groups. R202Q was the most prevalent mutation.

Functional and Structural Properties of Cytoplasmic Tropomyosin Isoforms Tpm1.8 and Tpm1.9.

The actin cytoskeleton is one of the most important players in cell motility, adhesion, division, and functioning. The regulation of specific microfilament formation largely determines cellular functions. The main actin-binding protein in animal cells is tropomyosin (Tpm). The unique structural and functional diversity of microfilaments is achieved through the diversity of Tpm isoforms. In our work, we studied the properties of the cytoplasmic isoforms Tpm1.8 and Tpm1.9. The results showed that these isoforms are highly thermostable and differ in the stability of their central and C-terminal fragments. The properties of these isoforms were largely determined by the 6th exons. Thus, the strength of the end-to-end interactions, as well as the affinity of the Tpm molecule for F-actin, differed between the Tpm1.8 and Tpm1.9 isoforms. They were determined by whether an alternative internal exon, 6a or 6b, was included in the Tpm isoform structure. The strong interactions of the Tpm1.8 and Tpm1.9 isoforms with F-actin led to the formation of rigid actin filaments, the stiffness of which was measured using an optical trap. It is quite possible that the structural and functional features of the Tpm isoforms largely determine the appearance of these isoforms in the rigid actin structures of the cell cortex.

Structure-Based Analysis of Cefaclor Pharmacokinetic Diversity According to Human Peptide Transporter-1 Genetic Polymorphism.

Cefaclor is a substrate of human-peptide-transporter-1 (PEPT1), and the impact of inter-individual pharmacokinetic variation due to genetic polymorphisms of solute-carrier-family-15-member-1 (SLC15A1) has been a topic of great debate. The main objective of this study was to analyze and interpret cefaclor pharmacokinetic variations according to genetic polymorphisms in SLC15A1 exons 5 and 16. The previous cefaclor bioequivalence results were integrated with additional SLC15A1 exons 5 and 16 genotyping results. An analysis of the structure-based functional impact of SLC15A1 exons 5 and 16 genetic polymorphisms was recently performed using a PEPT1 molecular modeling approach. In cefaclor pharmacokinetic analysis results according to SLC15A1 exons 5 and 16 genetic polymorphisms, no significant differences were identified between genotype groups. Furthermore, in the population pharmacokinetic modeling, genetic polymorphisms in SLC15A1 exons 5 and 16 were not established as effective covariates. PEPT1 molecular modeling results also confirmed that SLC15A1 exons 5 and 16 genetic polymorphisms did not have a significant effect on substrate interaction with cefaclor and did not have a major effect in terms of structural stability. This was determined by comprehensively considering the insignificant change in energy values related to cefaclor docking due to point mutations in SLC15A1 exons 5 and 16, the structural change in conformations confirmed to be less than 0.05 Å, and the relative stabilization of molecular dynamic simulation energy values. As a result, molecular structure-based analysis recently suggested that SLC15A1 exons 5 and 16 genetic polymorphisms of PEPT1 were limited to being the main focus in interpreting the pharmacokinetic diversity of cefaclor.