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1.
PLoS One ; 19(6): e0304141, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38843250

RESUMO

Lynch syndrome is caused by inactivating variants in DNA mismatch repair genes, namely MLH1, MSH2, MSH6 and PMS2. We have investigated five MLH1 and one MSH2 variants that we have identified in Turkish and Tunisian colorectal cancer patients. These variants comprised two small deletions causing frameshifts resulting in premature stops which could be classified pathogenic (MLH1 p.(His727Profs*57) and MSH2 p.(Thr788Asnfs*11)), but also two missense variants (MLH1 p.(Asn338Ser) and p.(Gly181Ser)) and two small, in-frame deletion variants (p.(Val647-Leu650del) and p.(Lys678_Cys680del)). For such small coding genetic variants, it is unclear if they are inactivating or not. We here provide clinical description of the variant carriers and their families, and we performed biochemical laboratory testing on the variant proteins to test if their stability or their MMR activity are compromised. Subsequently, we compared the results to in-silico predictions on structure and conservation. We demonstrate that neither missense alteration affected function, while both deletion variants caused a dramatic instability of the MLH1 protein, resulting in MMR deficiency. These results were consistent with the structural analyses that were performed. The study shows that knowledge of protein function may provide molecular explanations of results obtained with functional biochemical testing and can thereby, in conjunction with clinical information, elevate the evidential value and facilitate clinical management in affected families.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Proteína 1 Homóloga a MutL , Neoplasias Colorretais Hereditárias sem Polipose/genética , Humanos , Masculino , Proteína 1 Homóloga a MutL/genética , Feminino , Reparo de Erro de Pareamento de DNA/genética , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Adulto , Tunísia , Linhagem , Turquia , Idoso , Mutação de Sentido Incorreto
2.
Reprod Domest Anim ; 59(6): e14635, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38837470

RESUMO

A 1-year-old European shorthair male cat with a normally developed penis was subjected to genetic, endocrinological and histological studies due to unilateral cryptorchidism. The blood testosterone level was typical for males, while the level of anti-Mullerian hormone (AMH) was very low. Surgical removal of internal reproductive organs was followed by a histological study, which revealed inactive testicles with neoplastic changes and derivatives of Mullerian ducts. Cytogenetic analysis showed a normal XY sex chromosome complement and molecular analysis confirmed the presence of Y-linked genes (SRY and ZFY). Although the level of AMH was low, two normal copies of the AMH gene were found using droplet digital PCR (ddPCR). Analysis of the coding sequences of two candidate genes (AMH and AMHR2) for persistent Mullerian duct syndrome (PMDS) in the affected cat and in control male cats (n = 24) was performed using the Sanger sequencing method. In the affected cat, homozygosity was found for three novel missense variants in Exon 1 (one SNP) and Exon 5 (two SNPs) of AMH, but the same homozygous genotypes were also observed in one and two control cats, respectively, whose sex development was not examined. Three known synonymous variants with homozygous status were found in AMHR2. We conclude that the DNA variants identified in AMH and AMHR2 are not responsible for PMDS in the affected cat.


Assuntos
Hormônio Antimülleriano , Doenças do Gato , Receptores de Peptídeos , Receptores de Fatores de Crescimento Transformadores beta , Animais , Gatos , Masculino , Hormônio Antimülleriano/genética , Doenças do Gato/genética , Receptores de Peptídeos/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Criptorquidismo/genética , Criptorquidismo/veterinária , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/veterinária , Mutação , Mutação de Sentido Incorreto
4.
PLoS One ; 19(6): e0302643, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38829901

RESUMO

BACKGROUND: The A allele of rs373863828 in CREB3 regulatory factor is associated with high Body Mass Index, but lower odds of type 2 diabetes. These associations have been replicated elsewhere, but to date all studies have been cross-sectional. Our aims were (1) to describe the development of type 2 diabetes and change in fasting glucose between 2010 and 2018 among a longitudinal cohort of adult Samoans without type 2 diabetes or who were not using diabetes medications at baseline, and (2) to examine associations between fasting glucose rate-of-change (mmol/L per year) and the A allele of rs373863828. METHODS: We describe and test differences in fasting glucose, the development of type 2 diabetes, body mass index, age, smoking status, physical activity, urbanicity of residence, and household asset scores between 2010 and 2018 among a cohort of n = 401 adult Samoans, selected to have a ~2:2:1 ratio of GG:AG: AA rs373863828 genotypes. Multivariate linear regression was used to test whether fasting glucose rate-of-change was associated with rs373863828 genotype, and other baseline variables. RESULTS: By 2018, fasting glucose and BMI significantly increased among all genotype groups, and a substantial portion of the sample developed type 2 diabetes mellitus. The A allele was associated with a lower fasting glucose rate-of-change (ß = -0.05 mmol/L/year per allele, p = 0.058 among women; ß = -0.004 mmol/L/year per allele, p = 0.863 among men), after accounting for baseline variables. Mean fasting glucose and mean BMI increased over an eight-year period and a substantial number of individuals developed type 2 diabetes by 2018. However, fasting glucose rate-of-change, and type 2 diabetes development was lower among females with AG and AA genotypes. CONCLUSIONS: Further research is needed to understand the effect of the A allele on fasting glucose and type 2 diabetes development. Based on our observations that other risk factors increased over time, we advocate for the continued promotion for diabetes prevention and treatment programming, and the reduction of modifiable risk factors, in this setting.


Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Jejum , Humanos , Feminino , Diabetes Mellitus Tipo 2/genética , Masculino , Pessoa de Meia-Idade , Glicemia/metabolismo , Adulto , Jejum/sangue , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Alelos , Samoa , Estudos de Coortes , Índice de Massa Corporal , Genótipo , Estudos Longitudinais , Estudos Transversais , Idoso , Proteínas Supressoras de Tumor
5.
Sci Rep ; 14(1): 12732, 2024 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831004

RESUMO

Single nucleotide substitutions are the most common type of somatic mutations in cancer genome. The goal of this study was to use publicly available somatic mutation data to quantify negative and positive selection in individual lung tumors and test how strength of directional and absolute selection is associated with clinical features. The analysis found a significant variation in strength of selection (both negative and positive) among tumors, with median selection tending to be negative even though tumors with strong positive selection also exist. Strength of selection estimated as the density of missense mutations relative to the density of silent mutations showed only a weak correlation with tumor mutation burden. In the "all histology together" analysis we found that absolute strength of selection was strongly correlated with all clinically relevant features analyzed. In histology-stratified analysis selection was strongest in small cell lung cancer. Selection in adenocarcinoma was somewhat higher compared to squamous cell carcinoma. The study suggests that somatic mutation- based quantifying of directional and absolute selection in individual tumors can be a useful biomarker of tumor aggressiveness.


Assuntos
Neoplasias Pulmonares , Mutação , Seleção Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Biomarcadores Tumorais/genética , Mutação de Sentido Incorreto , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia
6.
J Exp Med ; 221(8)2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38869500

RESUMO

UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling.


Assuntos
Pérnio , Lúpus Eritematoso Sistêmico , Receptor 7 Toll-Like , Humanos , Lúpus Eritematoso Sistêmico/genética , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Feminino , Masculino , Pérnio/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mutação com Ganho de Função , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/metabolismo , Linhagem , Mutação de Sentido Incorreto , Células HEK293 , Lúpus Eritematoso Cutâneo/genética , Lúpus Eritematoso Cutâneo/patologia
7.
Mol Genet Genomic Med ; 12(6): e2466, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860480

RESUMO

BACKGROUND: Spinocerebellar ataxia 29 (SCA29) is a rare genetic disorder characterized by early-onset ataxia, gross motor delay, and infantile hypotonia, and is primarily associated with variants in the ITPR1 gene. Cases of SCA29 in Asia are rarely reported, limiting our understanding of this disease. METHODS: A female Korean infant, demonstrating clinical features of SCA29, underwent evaluation and rehabilitation at our outpatient clinic from the age of 3 months to the current age of 4 years. Trio-based genome sequencing tests were performed on the patient and her biological parents. RESULTS: The infant initially presented with macrocephaly, hypotonia, and nystagmus, with nonspecific findings on initial neuroimaging. Subsequent follow-up revealed gross motor delay, early onset ataxia, strabismus, and cognitive impairment. Further neuroimaging revealed atrophy of the cerebellum and vermis, and genetic analysis revealed a de novo pathogenic heterozygous c.800C>T, p.Thr267Met missense mutation in the ITPR1 gene (NM_001378452.1). CONCLUSION: This is the first reported case of SCA29 in a Korean patient, expanding the genetic and phenotypic spectrum of ITPR1-related ataxias. Our case highlights the importance of recognizing early-onset ataxic symptoms, central hypotonia, and gross motor delays with poor ocular fixation, cognitive deficits, and isolated cerebellar atrophy as crucial clinical indicators of SCA29.


Assuntos
Receptores de Inositol 1,4,5-Trifosfato , Mutação de Sentido Incorreto , Degenerações Espinocerebelares , Humanos , Feminino , Receptores de Inositol 1,4,5-Trifosfato/genética , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia , Pré-Escolar , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Lactente
8.
Proc Natl Acad Sci U S A ; 121(24): e2319301121, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38838011

RESUMO

Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with ADH1B expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete ADH1B in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in ADH1B (p.Arg313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein's dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid.


Assuntos
Adipócitos , Adipogenia , Álcool Desidrogenase , Humanos , Álcool Desidrogenase/metabolismo , Álcool Desidrogenase/genética , Adipogenia/genética , Adipócitos/metabolismo , Adipócitos/citologia , Tretinoína/metabolismo , Diferenciação Celular , Sistemas CRISPR-Cas , Mutação de Sentido Incorreto , Tecido Adiposo/metabolismo
9.
Virol J ; 21(1): 128, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840203

RESUMO

The envelope (E) protein of the Japanese encephalitis virus (JEV) is a key protein for virus infection and adsorption of host cells, which determines the virulence of the virus and regulates the intensity of inflammatory response. The mutation of multiple aa residues in the E protein plays a critical role in the attenuated strain of JEV. This study demonstrated that the Asp to Gly, Ser, and His mutation of the E389 site, respectively, the replication ability of the viruses in cells was significantly reduced, and the viral neuroinvasiveness was attenuated to different degrees. Among them, the mutation at E389 site enhanced the E protein flexibility contributed to the attenuation of neuroinvasiveness. In contrast, less flexibility of E protein enhanced the neuroinvasiveness of the strain. Our results indicate that the mechanism of attenuation of E389 aa mutation attenuates neuroinvasiveness is related to increased flexibility of the E protein. In addition, the increased flexibility of E protein enhanced the viral sensitivity to heparin inhibition in vitro, which may lead to a decrease in the viral load entering brain. These results suggest that E389 residue is a potential site affecting JEV virulence, and the flexibility of the E protein of aa at this site plays an important role in the determination of neuroinvasiveness.


Assuntos
Vírus da Encefalite Japonesa (Espécie) , Proteínas do Envelope Viral , Vírus da Encefalite Japonesa (Espécie)/genética , Vírus da Encefalite Japonesa (Espécie)/fisiologia , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/química , Animais , Linhagem Celular , Virulência , Replicação Viral , Encefalite Japonesa/virologia , Humanos , Heparina/farmacologia , Substituição de Aminoácidos , Mutação de Sentido Incorreto , Camundongos , Mutação , Fatores de Virulência/genética , Glicoproteínas de Membrana
10.
BMC Vet Res ; 20(1): 255, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867209

RESUMO

BACKGROUND: Porcine reproductive and respiratory syndrome virus 2 (PRRSV-2) infection during late gestation substantially lowers fetal viability and survival. In a previous genome-wide association study, a single nucleotide polymorphism on chromosome 7 was significantly associated with probability of fetuses being viable in response to maternal PRRSV-2 infection at 21 days post maternal inoculation. The iodothyronine deiodinase 2 (DIO2) gene, located ~ 14 Kilobase downstream of this SNP, was selected as a priority candidate related to fetal susceptibility following maternal PRRSV-2 infection. Our objectives were to identify mutation(s) within the porcine DIO2 gene and to determine if they were associated with fetal outcomes after PRRSV-2 challenge. Sequencing of the DIO2, genotyping identified variants, and association of DIO2 genotypes with fetal phenotypes including DIO2 mRNA levels, viability, survival, viral loads, cortisol and thyroid hormone levels, and growth measurements were conducted. RESULTS: A missense variant (p.Asn91Ser) was identified in the parental populations from two independent PRRSV-2 challenge trials. This variant was further genotyped to determine association with fetal PRRS outcomes. DIO2 mRNA levels in fetal heart and kidney differed by the genotypes of Asn91Ser substitution with significantly greater DIO2 mRNA expression in heterozygotes compared with wild-type homozygotes (P < 0.001 for heart, P = 0.002 for kidney). While Asn91Ser did not significantly alter fetal viability and growth measurements, interaction effects of the variant with fetal sex or trial were identified for fetal viability or crown rump length, respectively. However, this mutation was not related to dysregulation of the hypothalamic-pituitary-adrenal and thyroid axis, indicated by no differences in circulating cortisol, T4, and T3 levels in fetuses of the opposing genotypes following PRRSV-2 infection. CONCLUSIONS: The present study suggests that a complex relationship among DIO2 genotype, DIO2 expression, fetal sex, and fetal viability may exist during the course of fetal PRRSV infection. Our study also proposes the increase in cortisol levels, indicative of fetal stress response, may lead to fetal complications, such as fetal compromise, fetal death, or premature farrowing, during PRRSV infection.


Assuntos
Iodeto Peroxidase , Mutação de Sentido Incorreto , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Síndrome Respiratória e Reprodutiva Suína/genética , Síndrome Respiratória e Reprodutiva Suína/virologia , Feminino , Suínos , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Gravidez , Iodotironina Desiodinase Tipo II , Genótipo , Feto/virologia
11.
Orphanet J Rare Dis ; 19(1): 233, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867326

RESUMO

BACKGROUND: Two new missense variants (K68Q and R252H) of the protein kinase DYRK1B were recently reported to cause a monogenetic form of metabolic syndrome with autosomal dominant inheritance (AOMS3). RESULTS: Our in vitro functional analysis reveals that neither of these substitutions eliminates or enhances the catalytic activity of DYRK1B. DYRK1B-K68Q displays reduced nuclear translocation. CONCLUSION: The pathogenicity of DYRK1B variants does not necessarily correlate with the gain or loss of catalytic activity, but can be due to altered non-enzymatic characteristics such as subcellular localization.


Assuntos
Quinases Dyrk , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Humanos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Mutação de Sentido Incorreto/genética
12.
Mol Biol Rep ; 51(1): 753, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874636

RESUMO

BACKGROUND: The diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin production and secretion; low birthweight infants may have a reduced response to insulin. We report a novel missense ABCC8 variant associated with a clinical phenotype compatible with transient neonatal diabetes mellitus (TNDM) in a fetal growth restricted preterm infant. METHODS AND RESULTS: A preterm growth restricted infant experienced hyperglycemia from the first day of life, requiring insulin therapy on the 13th and 15th day of life and leading to the diagnosis of TNDM. Glycemic values normalized from the 35th day of life onwards. Genetic screening was performed by next generation sequencing, using a Clinical Exon panel of 4800 genes, filtered for those associated with the clinical presentation and by means of methylation-specific multiplex ligation-dependent probe amplification analysis to identify chromosomal aberrations at 6q24. Genetic tests excluded defects at 6q24 and were negative for KCNJ11, SLC2A2 (GLUT-2) and HNF1B, but revealed the presence of the heterozygous missense variant c.2959T > C (p.Ser987Pro) in ABCC8 gene. The presence of the variant was excluded in parents' DNA and the proband variant was then considered de novo. CONCLUSIONS: In our infant, the persistence of hyperglycemia beyond 3 weeks of life led us to the diagnosis of TNDM and to hypothesize a possible genetic cause. The genetic variant we found could be, most likely, the main cause of both FGR and TNDM.


Assuntos
Diabetes Mellitus , Retardo do Crescimento Fetal , Mutação de Sentido Incorreto , Receptores de Sulfonilureias , Humanos , Retardo do Crescimento Fetal/genética , Mutação de Sentido Incorreto/genética , Receptores de Sulfonilureias/genética , Recém-Nascido , Diabetes Mellitus/genética , Feminino , Masculino , Recém-Nascido Prematuro , Insulina/metabolismo , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/diagnóstico
13.
Environ Mol Mutagen ; 65(5): 179-186, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860553

RESUMO

Annotating genomic sequence alterations is sometimes a difficult decision, particularly in missense variants with uncertain pathogenic significance and also in those presumed as germline pathogenic variants. We here suggest that mutation spectrum may also be useful for judging them. From the public databases, 982 BRCA1/1861 BRCA2 germline missense variants and 294 BRCA1/420 BRCA2 somatic missense variants were obtained. We then compared their mutation spectra, i.e., the frequencies of two transition- and four transversion-type mutations, in each category. Intriguingly, in BRCA1 variants, A:T to C:G transversion, which was relatively frequent in the germline, was extremely rare in somatic, particularly breast cancer, cells (p = .03). Conversely, A:T to T:A transversion was most infrequent in the germline, but not rare in somatic cells. Thus, BRCA1 variants with A:T to T:A transversion may be suspected as somatic, and those with A:T to C:G as being in the germline. These tendencies of mutation spectrum may also suggest the biological and chemical origins of the base alterations. On the other hand, unfortunately, variants of uncertain significance (VUS) were not distinguishable by mutation spectrum. Our findings warrant further and more detailed studies.


Assuntos
Neoplasias da Mama , Mutação em Linhagem Germinativa , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação de Sentido Incorreto , Genes BRCA1 , Genes BRCA2
14.
Mol Genet Genomic Med ; 12(6): e2468, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38864382

RESUMO

BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly. METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members. RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species. CONCLUSION: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.


Assuntos
Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso , Linhagem , Polidactilia , Proteína Gli3 com Dedos de Zinco , Humanos , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo , Polidactilia/genética , Polidactilia/patologia , Masculino , Feminino , Proteínas do Tecido Nervoso/genética , Dedos de Zinco/genética , Fatores de Transcrição Kruppel-Like/genética , Dedos/anormalidades , Heterozigoto , População do Sudeste Asiático
15.
BMC Genom Data ; 25(1): 56, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858637

RESUMO

BACKGROUND: Polymorphisms in IL1B play a significant role in depression, multiple inflammatory-associated disorders, and susceptibility to infection. Functional non-synonymous SNPs (nsSNPs) result in changes in the encoded amino acids, potentially leading to structural and functional alterations in the mutant proteins. So far, most genetic studies have concentrated on SNPs located in the IL1B promoter region, without addressing nsSNPs and their association with multifactorial diseases. Therefore, this study aimed to explore the impact of deleterious nsSNPs retrieved from the dbSNP database on the structure and functions of the IL1B protein. RESULTS: Six web servers (SIFT, PolyPhen-2, PROVEAN, SNPs&GO, PHD-SNP, PANTHER) were used to analyze the impact of 222 missense SNPs on the function and structure of IL1B protein. Five novel nsSNPs (E100K, T240I, S53Y, D128Y, and F228S) were found to be deleterious and had a mutational impact on the structure and function of the IL1B protein. The I-mutant v2.0 and MUPro servers predicted that these mutations decreased the stability of the IL1B protein. Additionally, these five mutations were found to be conserved, underscoring their significance in protein structure and function. Three of them (T240I, D128Y, and F228S) were predicted to be cancer-causing nsSNPs. To analyze the behavior of the mutant structures under physiological conditions, we conducted a 50 ns molecular dynamics simulation using the WebGro online tool. Our findings indicate that the mutant values differ from those of the IL1B wild type in terms of RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds. CONCLUSIONS: This study provides valuable insights into nsSNPs located in the coding regions of IL1B, which lead to direct deleterious effects on the functional and structural aspects of the IL1B protein. Thus, these nsSNPs could be considered significant candidates in the pathogenesis of disorders caused by IL1B dysfunction, contributing to effective drug discovery and the development of precision medications. Thorough research and wet lab experiments are required to verify our findings. Moreover, bioinformatic tools were found valuable in the prediction of deleterious nsSNPs.


Assuntos
Biologia Computacional , Interleucina-1beta , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Biologia Computacional/métodos , Interleucina-1beta/genética , Mutação de Sentido Incorreto , Bases de Dados Genéticas
16.
Genes (Basel) ; 15(5)2024 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-38790209

RESUMO

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.


Assuntos
Epilepsia , Deficiência Intelectual , Espasticidade Muscular , Mutação de Sentido Incorreto , Linhagem , Ubiquitina-Proteína Ligases , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Ubiquitina-Proteína Ligases/genética , Masculino , Feminino , Epilepsia/genética , Paquistão , Espasticidade Muscular/genética , Transtornos Psicomotores/genética , Transtornos Psicomotores/patologia , Criança , Pré-Escolar
17.
BMC Res Notes ; 17(1): 131, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730444

RESUMO

OBJECTIVES: The crystal structure of the six protomers of gap junction protein beta 2 (GJB2) enables prediction of the effect(s) of an amino acid substitution, thereby facilitating investigation of molecular pathogenesis of missense variants of GJB2. This study mainly focused on R143W variant that causes hearing loss, and investigated the relationship between amino acid substitution and 3-D structural changes in GJB2. METHODS: Patients with nonsyndromic hearing loss who appeared to have two GJB2 pathogenic variants, including the R143W variant, were investigated. Because the X-ray crystal structure of the six protomers of the GJB2 protein is known, R143W and structurally related variants of GJB2 were modeled using this crystal structure as a template. The wild-type crystal structure and the variant computer-aided model were observed and the differences in molecular interactions within the two were analyzed. RESULTS: The predicted structure demonstrated that the hydrogen bond between R143 and N206 was important for the stability of the protomer structure. From this prediction, R143W related N206S and N206T variants showed loss of the hydrogen bond. CONCLUSION: Investigation of the genotypes and clinical data in patients carrying the R143W variant on an allele indicated that severity of hearing loss depends largely on the levels of dysfunction of the pathogenic variant on the allele, whereas a patient with the homozygous R143W variant demonstrated profound hearing loss. We concluded that these hearing impairments may be due to destabilization of the protomer structure of GJB2 caused by the R143W variant.


Assuntos
Conexina 26 , Conexinas , Perda Auditiva , Humanos , Conexina 26/genética , Conexinas/genética , Conexinas/química , Perda Auditiva/genética , Feminino , Masculino , Criança , Modelos Moleculares , Pré-Escolar , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Ligação de Hidrogênio , Cristalografia por Raios X , Adolescente , Adulto
18.
Mycopathologia ; 189(3): 40, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38704798

RESUMO

Candida parapsilosis complex has recently received special attention due to naturally occurring FKS1 polymorphism associated with high minimal inhibitory concentrations for echinocandin and the increase of clonal outbreaks of strains resistant to commonly used antifungals such as fluconazole. Despite the previous fact, little is known about the genetic mechanism associated with echinocandin resistance. Therefore, the present study was designed to investigate the mechanism of acquired echinocandin resistance in C. parapsilosis complex strains. A total of 15 clinical C. parapsilosis complex isolates were sub-cultured for 30 days at a low concentration of micafungin at ½ the lowest MIC value of the tested isolates (0.12 µg/ml). After culturing, all the isolates were checked phenotypically for antifungal resistance and genotypically for echinocandin resistance by checking FKS1 gene hot spot one (HS1) and HS2 mutations. In vitro induction of echinocandin resistance confirmed the rapid development of resistance at low concentration micafungin, with no difference among C. parapsilosis, C. metapsilosis, and C. orthopsilosis in the resistance development. For the first time we identified different FKS1 HS1 and or HS2 mutations responsible for echinocandin resistance such as R658S and L1376F in C. parapsilosis, S656X, R658X, R658T, W1370X, X1371I, V1371X, and R1373X (corresponding to their location in C. parapsilosis) in C. metapsilosis, and L648F and R1366H in C. orthopsilosis. Our results are of significant concern, since the rapid development of resistance may occur clinically after short-term exposure to antifungals as recently described in other fungal species with the potential of untreatable infections.


Assuntos
Antifúngicos , Candida parapsilosis , Farmacorresistência Fúngica , Equinocandinas , Glucosiltransferases , Humanos , Antifúngicos/farmacologia , Candida parapsilosis/genética , Candida parapsilosis/efeitos dos fármacos , Candidíase/microbiologia , Farmacorresistência Fúngica/genética , Equinocandinas/farmacologia , Proteínas Fúngicas/genética , Glucosiltransferases/genética , Micafungina/farmacologia , Testes de Sensibilidade Microbiana , Mutação , Mutação de Sentido Incorreto
19.
Nat Commun ; 15(1): 4380, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38782905

RESUMO

SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17ß-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.


Assuntos
Primatas , Animais , Humanos , Sequência de Aminoácidos , Estradiol/metabolismo , Células HEK293 , Hominidae/genética , Hominidae/metabolismo , Mutação de Sentido Incorreto , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Primatas/genética , Pseudogenes , Especificidade por Substrato
20.
Sci Rep ; 14(1): 10551, 2024 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719929

RESUMO

Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.


Assuntos
Códon , Perda Auditiva Neurossensorial , Fenótipo , Tubulina (Proteína) , Humanos , Feminino , Tubulina (Proteína)/genética , Tubulina (Proteína)/química , Masculino , Adulto , Perda Auditiva Neurossensorial/genética , Códon/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Criança , Linhagem , Adolescente , Substituição de Aminoácidos , Adulto Jovem , Retinose Pigmentar/genética
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