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International Journal of Molecular... Jun 2024Our study investigates the genetic mechanisms underlying the spotted leaf phenotype in rice, focusing on the mutant. This mutant is characterized by persistent...
Our study investigates the genetic mechanisms underlying the spotted leaf phenotype in rice, focusing on the mutant. This mutant is characterized by persistent reddish-brown leaf spots from the seedling stage to maturity, leading to extensive leaf necrosis. Using map-based cloning, we localized the responsible locus to a 330 Kb region on chromosome 2. We identified , named , as the causative gene. A point mutation in , substituting valine for glutamic acid, was identified as the critical factor for the phenotype. Functional complementation and the generation of CRISPR/Cas9-mediated knockout lines in the IR64 background confirmed the central role of OsRPT5A in controlling this trait. The qPCR results from different parts of the rice plant revealed that is constitutively expressed across various tissues, with its subcellular localization unaffected by the mutation. Notably, we observed an abnormal accumulation of reactive oxygen species (ROS) in mutants by examining the physiological indexes of leaves, suggesting a disruption in the ROS system. Complementation studies indicated OsRPT5A's involvement in ROS homeostasis and catalase activity regulation. Moreover, the mutant exhibited enhanced resistance to pv. (), highlighting OsRPT5A's role in rice pathogen resistance mechanisms. Overall, our results suggest that OsRPT5A plays a critical role in regulating ROS homeostasis and enhancing pathogen resistance in rice.
Topics: Oryza; Plant Leaves; Plant Proteins; Chromosome Mapping; Xanthomonas; Plant Diseases; Reactive Oxygen Species; Disease Resistance; Mutation; Phenotype; Gene Expression Regulation, Plant
PubMed: 38928342
DOI: 10.3390/ijms25126637 -
International Journal of Molecular... Jun 2024Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions,... (Review)
Review
Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for the exchange of solutes between the cytoplasm and the extracellular milieu, including messenger molecules involved in paracrine signalling. The synergistic action of membrane potential and Ca ions controls the gating of the large and relatively unselective pore of connexin HCs. The four orders of magnitude difference in gating sensitivity to the extracellular ([Ca]) and the cytosolic ([Ca]) Ca concentrations suggests that at least two different Ca sensors may exist. While [Ca] acts as a spatial modulator of the HC opening, which is most likely dependent on the cell layer, compartment, and organ, [Ca] triggers HC opening and the release of extracellular bursts of messenger molecules. Such molecules include ATP, cAMP, glutamate, NAD, glutathione, D-serine, and prostaglandins. Lost or abnormal HC regulation by Ca has been associated with several diseases, including deafness, keratitis ichthyosis, palmoplantar keratoderma, Charcot-Marie-Tooth neuropathy, oculodentodigital dysplasia, and congenital cataracts. The fact that both an increased and a decreased Ca sensitivity has been linked to pathological conditions suggests that Ca in healthy cells finely tunes the normal HC function. Overall, further investigation is needed to clarify the structural and chemical modifications of connexin HCs during [Ca] and [Ca] variations. A molecular model that accounts for changes in both Ca and the transmembrane voltage will undoubtedly enhance our interpretation of the experimental results and pave the way for developing therapeutic compounds targeting specific HC dysfunctions.
Topics: Connexins; Humans; Calcium; Animals; Gap Junctions; Calcium Signaling
PubMed: 38928300
DOI: 10.3390/ijms25126594 -
International Journal of Molecular... Jun 2024Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of...
Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with mutations and broaden the clinical spectrum. We suggest screening for in recessive CMT patients with complex phenotypes of ataxia and spasticity.
Topics: Humans; Male; Charcot-Marie-Tooth Disease; Female; Mutation; Adult; Republic of Korea; Muscle Spasticity; Heterozygote; Cohort Studies; Middle Aged; Magnetic Resonance Imaging; Heat-Shock Proteins; Pedigree; Exome Sequencing; Cerebellar Ataxia; Phenotype; Adolescent; Young Adult
PubMed: 38928084
DOI: 10.3390/ijms25126378 -
Genes Jun 2024Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP)...
Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP) tests have become clinically available. In this study, we aimed to clarify the significance of multi-CGP testing of BC by using the large clinical dataset from The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database in Japan. A total of 3744 BC cases were extracted from the C-CAT database, which enrolled 60,250 patients between June 2019 and October 2023. Of the 3744 BC cases, a total of 3326 cases for which the C-CAT included information on ER, PR, and HER2 status were classified into four subtypes, including TNBC, HR+/HER2-, HR+/HER2+, and HR-/HER2+. Comparisons between groups were performed by the χ test or Fisher's exact test using EZR. Kaplan-Meier curves were created using the log-rank test. : Of all 3326 cases analyzed, 1114 (33.5%) were TNBC cases, HR+/HER2- accounted for 1787 cases (53.7%), HR+/HER2+ for 260 cases (7.8%), and HR-/HER2+ for 165 cases (5.0%). Genetic abnormalities were most frequently detected in (58.0%), (35.5%), (18.7%), (15.5%), and (15.1%) across all BCs. The rate of TMB-High was 12.3%, and the rate of MSI-High was 0.3%, in all BC cases. Therapeutic drugs were proposed for patients with mutations in six genes: , , , , , and . The prognoses of HR+/HER2- cases were significantly ( = 0.044) better in the treated group than in the untreated group. : These findings suggest that cancer gene panel testing is useful for HR+/HER2- cases.
Topics: Humans; Female; Japan; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Aged; Adult; Retrospective Studies; Biomarkers, Tumor; Receptors, Estrogen; Receptors, Progesterone; Aged, 80 and over; Prognosis; Mutation; Gene Expression Profiling; Class I Phosphatidylinositol 3-Kinases
PubMed: 38927728
DOI: 10.3390/genes15060792 -
Genes Jun 2024Mosaicism for autosomal trisomy is uncommon in clinical practice. However, despite its rarity among both prenatally and postnatally diagnoses, there are a large number...
Mosaicism for autosomal trisomy is uncommon in clinical practice. However, despite its rarity among both prenatally and postnatally diagnoses, there are a large number of characterized and published cases. Surprisingly, in contrast to regular trisomies, no attempts at systematic analyses of mosaic carriers' demographics were undertaken. This is the first study aimed to address this gap. For that, we have screened more than eight hundred publications on mosaic trisomies, reviewing data including gender and clinical status of mosaic carriers, maternal age and reproductive history. In total, 596 publications were eligible for analysis, containing data on 948 prenatal diagnoses, including true fetal mosaicism (TFM) and confined placental mosaicism (CPM), and on 318 cases of postnatally detected mosaicism (PNM). No difference was found in maternal age between normal pregnancy outcomes with appropriate birth weight and those with intrauterine growth restriction. Unexpectedly, a higher proportion of advanced maternal ages (AMA) was found in normal outcomes compared to abnormal ones (abnormal fetus or newborn) and fetal losses, 73% vs. 56% and 50%, = 0.0015 and 0.0011, correspondingly. Another intriguing finding was a higher AMA proportion in mosaic carriers with concomitant uniparental disomy (UPD) for chromosomes 7, 14, 15, and 16 compared to carriers with biparental disomy (BPD) (72% vs. 58%, 92% vs. 55%, 87% vs. 78%, and 65% vs. 24%, correspondingly); overall figures were 78% vs. 48%, 0.0026. Analysis of reproductive histories showed a very poor reporting but almost two-fold higher rate of mothers reporting a previous fetal loss from PNM cohort (in which almost all patients were clinically abnormal) compared to mothers from the TFM and CPM cohorts (with a large proportion of normal outcomes), 30% vs. 16%, = 0.0072. The occurrence of a previous pregnancy with a chromosome abnormality was 1 in 13 in the prenatal cohort and 1 in 16 in the postnatal cohort, which are five-fold higher compared to published studies on non-mosaic trisomies. We consider the data obtained in this study to be preliminary despite the magnitude of the literature reviewed since reporting of detailed data was mostly poor, and therefore, the studied cohorts do not represent "big data". Nevertheless, the information obtained is useful both for clinical genetic counseling and for modeling further studies.
Topics: Humans; Mosaicism; Maternal Age; Female; Pregnancy; Trisomy; Reproductive History; Adult; Prenatal Diagnosis; Uniparental Disomy; Male
PubMed: 38927714
DOI: 10.3390/genes15060778 -
Genes Jun 2024The retinal features of Bardet-Biedl syndrome (BBS) are insufficiently characterized in Arab populations. This retrospective study investigated the retinal features and...
The retinal features of Bardet-Biedl syndrome (BBS) are insufficiently characterized in Arab populations. This retrospective study investigated the retinal features and genotypes of BBS in Saudi patients managed at a single tertiary eye care center. Data analysis of the identified 46 individuals from 31 families included visual acuity (VA), systemic manifestations, multimodal retinal imaging, electroretinography (ERG), family pedigrees, and genotypes. Patients were classified to have cone-rod, rod-cone, or generalized photoreceptor dystrophy based on the pattern of macular involvement on the retinal imaging. Results showed that nyctalopia and subnormal VA were the most common symptoms with 76% having VA ≤ 20/200 at the last visit (age: 5-35). Systemic features included obesity 91%, polydactyly 56.5%, and severe cognitive impairment 33%. The predominant retinal phenotype was cone-rod dystrophy 75%, 10% had rod-cone dystrophy and 15% had generalized photoreceptor dystrophy. ERGs were undetectable in 95% of patients. Among the 31 probands, 61% had biallelic variants in BBSome complex genes, 32% in chaperonin complex genes, and 6% had biallelic variants in ; including six previously unreported variants. Interfamilial and intrafamilial variabilities were noted, without a clear genotype-phenotype correlation. Most BBS patients had advanced retinopathy and were legally blind by early adulthood, indicating a narrow therapeutic window for rescue strategies.
Topics: Humans; Bardet-Biedl Syndrome; Male; Saudi Arabia; Female; Child; Adolescent; Adult; Child, Preschool; Mutation; Young Adult; Pedigree; Retrospective Studies; Electroretinography; Phenotype; Visual Acuity; Retina; ADP-Ribosylation Factors
PubMed: 38927698
DOI: 10.3390/genes15060762 -
Genes Jun 2024Chromosomal translocations can result in phenotypic effects of varying severity, depending on the position of the breakpoints and the rearrangement of genes within the...
Chromosomal translocations can result in phenotypic effects of varying severity, depending on the position of the breakpoints and the rearrangement of genes within the interphase nucleus of the translocated chromosome regions. Balanced translocations are often asymptomatic phenotypically and are typically detected due to a decrease in fertility resulting from issues during meiosis. Robertsonian translocations are among the most common chromosomal abnormalities, often asymptomatic, and can persist in the population as a normal polymorphism. We serendipitously discovered a Robertsonian translocation between chromosome 21 and chromosome 22, which is inherited across three generations without any phenotypic effect, notably only in females. In situ hybridization with alpha-satellite DNAs revealed the presence of both centromeric sequences in the translocated chromosome. The reciprocal translocation resulted in a partial deletion of the short arm of both chromosomes 21, and 22, with the genes remaining present in the middle part of the new metacentric chromosome. The rearrangement did not cause alterations to the long arm. The spread of an asymptomatic heterozygous chromosomal polymorphism in a population can lead to mating between heterozygous individuals, potentially resulting in offspring with a homozygous chromosomal configuration for the anomaly they carry. This new karyotype may not produce phenotypic effects in the individual who presents it. The frequency of karyotypes with chromosomal rearrangements in asymptomatic heterozygous form in human populations is likely underestimated, and molecular karyotype by array Comparative Genomic Hybridization (array-CGH) analysis does not allow for the identification of this type of chromosomal anomaly, making classical cytogenetic analysis the preferred method for obtaining clear results on a karyotype carrying a balanced rearrangement.
Topics: Humans; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 22; In Situ Hybridization, Fluorescence; Karyotype; Karyotyping; Phenotype; Translocation, Genetic
PubMed: 38927657
DOI: 10.3390/genes15060722 -
Genes May 2024Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The gene...
Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The gene located on chromosome 12 encodes for myogenic factor 5 (MYF5), which has a role in skeletal and extraocular muscle development and rib formation. Variants in were found to cause external ophthalmoplegia with rib and vertebral anomalies (EORVA), a rare recessive condition. To date, three homozygous variants in have been reported to cause EORVA in six members of four unrelated families. Here, we present a novel homozygous frameshift variant, c.596dupA p. (Asn199Lysfs*49), causing premature protein termination and presenting with external ophthalmoplegia, ptosis, and scoliosis in three siblings from a consanguineous family of Pakistani origin. With four variants now discovered, genetic testing and paediatric assessment for extra-ocular features should be considered in all cases of congenital ophthalmoplegia.
Topics: Humans; Frameshift Mutation; Male; Female; Myogenic Regulatory Factor 5; Ophthalmoplegia; Ribs; Pedigree; Spine; Child; Homozygote
PubMed: 38927634
DOI: 10.3390/genes15060699 -
Genes May 2024Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the or variants. These variants modify the preferred substrate of...
Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the or variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Identifying new or "" variants raises the question as to their pathogenicity. This work focused on characterizing six new variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Variants from six patients with HSAN1 were studied. , CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two variants were newly described as pathogenic: NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.
Topics: Humans; Serine C-Palmitoyltransferase; Hereditary Sensory and Autonomic Neuropathies; Mutation, Missense; Male; Female; Sphingolipids; Adult; Middle Aged
PubMed: 38927628
DOI: 10.3390/genes15060692 -
Genes May 2024The gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the... (Review)
Review
The gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the variants in the C-terminal DNA-binding domain associated with non-syndromic congenital cataracts and describe a patient with a novel, disease-causing de novo missense variant. Published reports of C-terminal variants and their associated congenital cataracts and ophthalmic findings were reviewed. The patient we present and his biological parents had genetic testing via a targeted gene panel followed by trio-based whole exome sequencing. A 4-year-old patient with a history of bilateral nuclear and cortical cataracts was found to have a novel, likely pathogenic de novo variant in , NM_005360.5:c.922A>G (p.Lys308Glu). No syndromic findings or anterior segment abnormalities were identified. We report the novel missense variant, c.922A>G (p.Lys308Glu), in the C-terminal DNA-binding domain of classified as likely pathogenic and associated with non-syndromic bilateral congenital cataracts.
Topics: Humans; Cataract; Proto-Oncogene Proteins c-maf; Mutation, Missense; Male; Child, Preschool; Protein Domains; Exome Sequencing
PubMed: 38927621
DOI: 10.3390/genes15060686