scholarly journals Novel Mutation in CRYBB3 Causing Pediatric Cataract and Microphthalmia

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1069
Author(s):  
Olivia A. Zin ◽  
Luiza M. Neves ◽  
Fabiana L. Motta ◽  
Dafne D. G. Horovitz ◽  
Leticia Guida ◽  
...  
Keyword(s):  
Amino Acid ◽  
Bioinformatics Analysis ◽  
Novel Mutation ◽  
Family Members ◽  
Missense Variant ◽  
Pediatric Cataract ◽  
First Time ◽  
Mutant Genes ◽  
Generation Sequencing ◽  
Childhood Cataract

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in CRYBB3 in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of CRYBB3 is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia.

scholarly journals High Genomic Variability in Equine Infectious Anemia Virus Obtained from Naturally Infected Horses in Pantanal, Brazil: An Endemic Region Case

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 207 ◽  
Author(s):  
Camila Dantas Malossi ◽  
Eduardo Gorzoni Fioratti ◽  
Jedson Ferreira Cardoso ◽  
Angelo Jose Magro ◽  
Erna Geessien Kroon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Equine Infectious Anemia Virus ◽  
Genomic Sequences ◽  
Endemic Region ◽  
Viral Genomes ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Next Generation Sequencing Ngs ◽  
First Time ◽  
Generation Sequencing

Equine infectious anemia virus (EIAV) is a persistent lentivirus that causes equine infectious anemia (EIA). In Brazil, EIAV is endemic in the Pantanal region, and euthanasia is not mandatory in this area. All of the complete genomic sequences from field viruses are from North America, Asia, and Europe, and only proviral genomic sequences are available. Sequences from Brazilian EIAV are currently available only for gag and LTR regions. Thus, the present study aimed for the first time to sequence the entire EIAV genomic RNA in naturally infected horses from an endemic area in Brazil. RNA in plasma from naturally infected horses was used for next-generation sequencing (NGS), and gaps were filled using Sanger sequencing methodology. Complete viral genomes of EIAV from two horses were obtained and annotated (Access Number: MN560970 and MN560971). Putative genes were analyzed and compared with previously described genes, showing conservation in gag and pol genes and high variations in LTR and env sequences. Amino acid changes were identified in the p26 protein, one of the most common targets used for diagnosis, and p26 molecular modelling showed surface amino acid alterations in some epitopes. Brazilian genome sequences presented 88.6% nucleotide identity with one another and 75.8 to 77.3% with main field strains, such as EIAV Liaoning, Wyoming, Ireland, and Italy isolates. Furthermore, phylogenetic analysis suggested that this Brazilian strain comprises a separate monophyletic group. These results may help to better characterize EIAV and to overcome the challenges of diagnosing and controlling EIA in endemic regions.

Identification of a Disease-Causing Mutation in a Chinese Patient with Retinitis Pigmentosa by Targeted Next-Generation Sequencing

2017 ◽  
Vol 27 (6) ◽  
pp. 791-796 ◽  
Author(s):  
Jianping Xiao ◽  
Xueqin Guo ◽  
Yong Wang ◽  
Mingkun Shao ◽  
Xiaoming Wei ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Sanger Sequencing ◽  
Bioinformatics Analysis ◽  
Family Members ◽  
Chinese Patient ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

Purpose To identify disease-causing mutations in a Chinese patient with retinitis pigmentosa (RP). Methods A detailed clinical examination was performed on the proband. Targeted next-generation sequencing (NGS) combined with bioinformatics analysis was performed on the proband to detect candidate disease-causing mutations. Sanger sequencing was performed on all subjects to confirm the candidate mutations and assess cosegregation within the family. Results Clinical examinations of the proband showed typical characteristics of RP. Three candidate heterozygous mutations in 3 genes associated with RP were detected in the proband by targeted NGS. The 3 mutations were confirmed by Sanger sequencing and the deletion (c.357_358delAA) in PRPF31 was shown to cosegregate with RP phenotype in 7 affected family members, but not in 3 unaffected family members. Conclusions The deletion (c.357_358delAA) in PRPF31 was the disease-causing mutation for the proband and his affected family members with RP. To our knowledge, this is the second report of the deletion and the first report of the other 2 mutations in the Chinese population. Targeted NGS combined with bioinformatics analysis proved to be an effective molecular diagnostic tool for RP.

scholarly journals Identification of Three FBN1 Mutations in Chinese Patients with Typical or Incomplete Marfan Syndrome by Whole-Exome Sequencing

2020 ◽  
Vol 5 (1) ◽  
pp. 19-26
Author(s):  
Guangming Fang ◽  
Jinxin Miao ◽  
Ying Peng ◽  
Yafei Zhai ◽  
Chuchu Wang ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Novel Mutation ◽  
Family Members ◽  
Chinese Patients ◽  
Chinese Families ◽  
Whole Exome ◽  
The Family ◽  
Functional Consequences ◽  
The Relationship ◽  
Generation Sequencing

Objective: The purpose of this work was to obtain the phenotypes and detect potential mutations in three Chinese patients with Marfan syndrome (MFS) or incomplete MFS phenotypes.Methods: Three unrelated patients with a definite or suspected clinical diagnosis of MFS and their family members were recruited for research. Genomic DNA was extracted from peripheral blood of these patients and their family members. All the exons were sequenced by next-generation sequencing and the variants were further validated by Sanger sequencing. The functional consequences of the mutations were analyzed with various genomic resources and bioinformatics tools.Results: Three FBN1 mutations were identified in the three patients, including one novel mutation (2125G > A) and two previously reported mutations (4786C > T and 6325C > T). It was interesting to note that the parents of these patients were normal as assessed by clinical features or genetic testing, but all these mutations were detected in their offspring, except for the variant 6325C > T. We also found that a few young members of the family of probands (proband 1 and proband 2) have exhibited no manifestations of MFS so far, although they carry the same disease-causing mutation.Conclusions: We found three FBN1 mutations in three unrelated Chinese families with MFS by genome sequencing, and the relationship between genotypes and phenotypes in MFS patients needs further exploration.

scholarly journals Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Gerhard Binder ◽  
Julian Ziegler ◽  
Roland Schweizer ◽  
Wisam Habhab ◽  
Tobias B. Haack ◽  
...  
Keyword(s):  
Amino Acid ◽  
Adrenal Insufficiency ◽  
Novel Mutation ◽  
Hot Spot ◽  
Missense Variant ◽  
Single Family ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Functional Region ◽  
Silver Russell Syndrome

Abstract Background Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. Results Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. Conclusions In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.

Single Amino Acid Based Self-Assemblies of Cysteine and Methionine

2018 ◽  
Author(s):  
Nidhi Gour ◽  
Bharti Koshti ◽  
Chandra Kanth P. ◽  
Dhruvi Shah ◽  
Vivek Shinh Kshatriya ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Self Assembly ◽  
Aromatic Amino Acids ◽  
Neutral Condition ◽  
Single Amino Acid ◽  
Binding Assays ◽  
Human Neuroblastoma ◽  
Cytotoxicity Assays ◽  
First Time

We report for the very first time self-assembly of Cysteine and Methionine to discrenible strucutres under neutral condition. To get insights into the structure formation, thioflavin T and Congo red binding assays were done which revealed that aggregates may not have amyloid like characteristics. The nature of interactions which lead to such self-assemblies was purported by coincubating assemblies in urea and mercaptoethanol. Further interaction of aggregates with short amyloidogenic dipeptide diphenylalanine (FF) was assessed. While cysteine aggregates completely disrupted FF fibres, methionine albeit triggered fibrillation. The cytotoxicity assays of cysteine and methionine structures were performed on Human Neuroblastoma IMR-32 cells which suggested that aggregates are not cytotoxic in nature and thus, may not have amyloid like etiology. The results presented in the manuscript are striking, since to the best of our knowledge,this is the first report which demonstrates that even non-aromatic amino acids (cysteine and methionine) can undergo spontaneous self-assembly to form ordered aggregates.

scholarly journals A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

2021 ◽  
Author(s):  
Barbara Vona ◽  
Neda Mazaheri ◽  
Sheng-Jia Lin ◽  
Lucy A. Dunbar ◽  
Reza Maroofian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Amino Acid ◽  
Rna Splicing ◽  
Stop Codon ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Deafness Gene ◽  
Expression Studies ◽  
Hearing Function

AbstractDeafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

Access to 2-Arylquinazolines via Catabolism/Reconstruction of Amino Acids with Insertion of Dimethyl Sulfoxide

2021 ◽  
Author(s):  
Jin-Tian Ma ◽  
Li-Sheng Wang ◽  
Zhi Chai ◽  
Xin-Feng Chen ◽  
Bo-Cheng Tang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Dimethyl Sulfoxide ◽  
Nitrogen Source ◽  
Carbon And Nitrogen ◽  
First Time

Quinazoline skeletons are synthesized by amino acids catabolism/reconstruction combined with dimethyl sulfoxide insertion/cyclization for the first time. The amino acid acts as a carbon and nitrogen source through HI-mediated catabolism...

scholarly journals Identification of a Novel Missense KRT12 Mutation in a Vietnamese Family with Meesmann Corneal Dystrophy

2020 ◽  
Vol 11 (1) ◽  
pp. 120-126
Author(s):  
Pham Ngoc Dong ◽  
Le Xuan Cung ◽  
Tran Khanh Sam ◽  
Do Thi Thuy Hang ◽  
Doug D. Chung ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Novel Mutation ◽  
Family Members ◽  
Corneal Dystrophy ◽  
Slit Lamp ◽  
Slit Lamp Examination ◽  
Corneal Epithelial ◽  
Epithelial Phenotype ◽  
History Of ◽  
Characteristic Features

Meesmann epithelial corneal dystrophy (MECD) is a rare dominantly inherited disorder that is characterized by corneal epithelial microcysts and is associated with mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes. In this study, we report a novel mutation in the KRT12 gene in a Vietnamese pedigree with MECD. Slit-lamp examination was performed on each of the 7 recruited members of a Vietnamese family to identify characteristic features of MECD. After informed consent was obtained from each individual, genomic DNA was isolated from saliva samples and screening of KRT3and KRT12 genes was performed by Sanger sequencing. The proband, a 31-year-old man, complained of a 1-year history of eye irritation and photophobia. Slit-lamp examination revealed intraepithelial microcysts involving only the corneal periphery in each eye with clear central corneas and no stromal or endothelial involvement. Three family members demonstrated similar intraepithelial microcysts, but with diffuse involvement, extended from limbus to limbus. Sanger sequencing of KRT3 (exon 7) and KRT12 (exons 1 and 6) in the proband revealed a novel heterozygous KRT12 variant (c.1273G>A [p.Glu425Lys]) that was present in the three affected family members but was absent in the three family members with clear corneas. This study is the first report of a Vietnamese family affected with MECD, associated with an atypical peripheral corneal epithelial phenotype in the proband and a novel mutation in KRT12.

scholarly journals Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma

2013 ◽  
Vol 2 (2) ◽  
pp. 104-111 ◽  
Author(s):  
Joakim Crona ◽  
Alberto Delgado Verdugo ◽  
Dan Granberg ◽  
Staffan Welin ◽  
Peter Stålberg ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Screening ◽  
Bioinformatics Analysis ◽  
Cost Effective ◽  
Susceptibility Genes ◽  
Next Generation ◽  
Clinical Genetic ◽  
Cost Effective Method ◽  
Agilent Sureselect ◽  
Generation Sequencing

BackgroundRecent findings have shown that up to 60% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are caused by germline or somatic mutations in one of the 11 hitherto known susceptibility genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A (EPAS1), RET, NF1, TMEM127 and MAX. This list of genes is constantly growing and the 11 genes together consist of 144 exons. A genetic screening test is extensively time consuming and expensive. Hence, we introduce next-generation sequencing (NGS) as a time-efficient and cost-effective alternative.MethodsTumour lesions from three patients with apparently sporadic PCC were subjected to whole exome sequencing utilizing Agilent Sureselect target enrichment system and Illumina Hi seq platform. Bioinformatics analysis was performed in-house using commercially available software. Variants in PCC and PGL susceptibility genes were identified.ResultsWe have identified 16 unique genetic variants in PCC susceptibility loci in three different PCC, spending less than a 30-min hands-on, in-house time. Two patients had one unique variant each that was classified as probably and possibly pathogenic: NF1 Arg304Ter and RET Tyr791Phe. The RET variant was verified by Sanger sequencing.ConclusionsNGS can serve as a fast and cost-effective method in the clinical genetic screening of PCC. The bioinformatics analysis may be performed without expert skills. We identified process optimization, characterization of unknown variants and determination of additive effects of multiple variants as key issues to be addressed by future studies.

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