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1.
Genes (Basel) ; 15(6)2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38927727

RESUMO

Mutations in the gene SCAPER (S phase Cyclin A-Associated Protein residing in the Endoplasmic Reticulum) have recently been associated with retinitis pigmentosa (RP) and intellectual disability (ID). In 2011, a possible involvement of SCAPER in human diseases was discovered for the first time due to the identification of a homozygous mutation causing ID in an Iranian family. Later, five studies were published in 2019 that described patients with autosomal recessive syndromic retinitis pigmentosa (arRP) accompanied by ID and attention-deficit/hyperactivity disorder (ADHD). This present study describes three patients from an Arab consanguineous family in Israel with similar clinical features of the SCAPER syndrome. In addition, new manifestations of ocular symptoms, nystagmus, glaucoma, and elevator palsy, were observed. Genetic testing of the patients and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Phenotypic and genotypic descriptions for all available cases described in the literature including our current three cases (37 cases) were carried out, in addition to a bioinformatics analysis for all the genetic variants that was undertaken. Our study confirms and extends the clinical manifestations of SCAPER-related disorders.


Assuntos
Biologia Computacional , Deficiência Intelectual , Mutação , Linhagem , Fenótipo , Retinose Pigmentar , Adolescente , Adulto , Feminino , Humanos , Proteínas de Transporte/genética , Biologia Computacional/métodos , Consanguinidade , Sequenciamento do Exoma , Genes Recessivos , Homozigoto , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Retinose Pigmentar/genética , Retinose Pigmentar/patologia
2.
Mol Biol Rep ; 51(1): 714, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824264

RESUMO

BACKGROUND: NOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance. METHODS AND RESULTS: Whole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center. CONCLUSION: The findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders.


Assuntos
Sequenciamento do Exoma , Genes Recessivos , Linhagem , Fenótipo , Receptor Notch3 , Humanos , Receptor Notch3/genética , Masculino , Feminino , Sequenciamento do Exoma/métodos , Genes Recessivos/genética , Adulto , Estudos de Associação Genética , CADASIL/genética , Imageamento por Ressonância Magnética/métodos , Alelos , Homozigoto , Consanguinidade , Mutação com Perda de Função/genética , Mutação/genética , Heterozigoto
4.
Theor Appl Genet ; 137(6): 126, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38727833

RESUMO

KEY MESSAGE: The gene controlling pink flesh in watermelon was finely mapped to a 55.26-kb region on chromosome 6. The prime candidate gene, Cla97C06G122120 (ClPPR5), was identified through forward genetics. Carotenoids offer numerous health benefits; while, they cannot be synthesized by the human body. Watermelon stands out as one of the richest sources of carotenoids. In this study, genetic generations derived from parental lines W15-059 (red flesh) and JQ13-3 (pink flesh) revealed the presence of the recessive gene Clpf responsible for the pink flesh (pf) trait in watermelon. Comparative analysis of pigment components and microstructure indicated that the disparity in flesh color between the parental lines primarily stemmed from variations in lycopene content, as well as differences in chromoplast number and size. Subsequent bulk segregant analysis (BSA-seq) and genetic mapping successfully narrowed down the Clpf locus to a 55.26-kb region on chromosome 6, harboring two candidate genes. Through sequence comparison and gene expression analysis, Cla97C06G122120 (annotated as a pentatricopeptide repeat, PPR) was predicted as the prime candidate gene related to pink flesh trait. To further investigate the role of the PPR gene, its homologous gene in tomato was silenced using a virus-induced system. The resulting silenced fruit lines displayed diminished carotenoid accumulation compared with the wild-type, indicating the potential regulatory function of the PPR gene in pigment accumulation. This study significantly contributes to our understanding of the forward genetics underlying watermelon flesh traits, particularly in relation to carotenoid accumulation. The findings lay essential groundwork for elucidating mechanisms governing pigment synthesis and deposition in watermelon flesh, thereby providing valuable insights for future breeding strategies aimed at enhancing fruit quality and nutritional value.


Assuntos
Mapeamento Cromossômico , Citrullus , Frutas , Fenótipo , Pigmentação , Proteínas de Plantas , Citrullus/genética , Citrullus/metabolismo , Pigmentação/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Frutas/genética , Genes de Plantas , Carotenoides/metabolismo , Genes Recessivos , Regulação da Expressão Gênica de Plantas , Cromossomos de Plantas/genética , Licopeno/metabolismo
5.
Mol Biol Rep ; 51(1): 626, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38717621

RESUMO

BACKGROUND: Bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is one of the most devastating diseases of rice leading to huge yield losses in Southeast Asia. The recessive resistance gene xa-45(t) from Oryza glaberrima IRGC102600B, mapped on rice chromosome 8, spans 80 Kb with 9 candidate genes on Nipponbare reference genome IRGSP-1.0. The xa-45(t) gene provides durable resistance against all the ten Xanthomonas pathotypes of Northern India, thus aiding in the expansion of recessive bacterial blight resistance gene pool. Punjab Rice PR127, carrying xa-45(t), was released for wider use in breeding programs. This study aims to precisely locate the target gene among the 9 candidates conferring resistance to bacterial blight disease. METHODS AND RESULTS: Sanger sequencing of all nine candidate genes revealed seven SNPs and an Indel between the susceptible parent Pusa 44 and the resistant introgression line IL274. The genotyping with polymorphic markers identified three recombinant breakpoints for LOC_Os08g42370, and LOC_Os08g42400, 15 recombinants for LOC_Os08g423420 and 26 for LOC_Os08g42440 out of 190 individuals. Relative expression analysis across six time intervals (0, 8, 24, 48, 72, and 96 h) after bacterial blight infection showed over expression of LOC_Os08g42410-specific transcripts in IL274 compared to Pusa 44, with a significant 4.46-fold increase observed at 72 h post-inoculation. CONCLUSIONS: The Indel marker at the locus LOC_Os08g42410 was found co-segregating with the phenotype, suggesting its candidacy towards xa-45(t). The transcript abundance assay provides strong evidence for the involvement of LOC_Os08g42410 in the resistance conferred by the bacterial blight gene xa-45(t).


Assuntos
Mapeamento Cromossômico , Resistência à Doença , Oryza , Doenças das Plantas , Mapeamento Cromossômico/métodos , Cromossomos de Plantas/genética , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas/genética , Genes de Plantas/genética , Genes Recessivos , Genótipo , Oryza/genética , Oryza/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Polimorfismo de Nucleotídeo Único/genética , Xanthomonas/patogenicidade
6.
Gene ; 924: 148558, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-38740353

RESUMO

Recessive genic male sterility (RGMS) provides an effective approach for the commercial exploitation of heterosis, especially in Brassica crops. Although some artificial RGMS mutants have been reported in B. rapa, no causal genes derived from these natural mutants have been identified so far. In this study, a spontaneous RGMS mutant Bcajh97-01A derived from the 'Aijiaohuang' line traced back to the 1980 s was identified. Genetic analysis revealed that the RGMS trait was controlled by a single locus in the Bcajh97-01A/B system. Bulk segregant analysis (BSA) in combination with linkage analysis was employed to delimit the causal gene to an approximate 129 kb interval on chromosome A02. The integrated information of transcriptional levels and the predicted genes in the target region indicated that the Brmmd1 (BraA02g017420) encoding a PHD-containing nuclear protein was the most likely candidate gene. A 374 bp miniature inverted-repeat transposable element (MITE) was inserted into the first exon to prematurely stop the Brmmd1 gene translation, thus blocking the normal expression of this gene at the tetrad stage in the Bcajh97-01A. Additionally, a co-segregating structure variation (SV) marker was developed to rapidly screen the RGMS progenies from Bcajh97-01A/B system. Our findings reveal that BraA02g017420 is the causal gene responsible for the RGMS trait. This study lays a foundation for marker-assisted selection and further molecular mechanism exploration of pollen development in B. rapa.


Assuntos
Brassica rapa , Mapeamento Cromossômico , Genes Recessivos , Infertilidade das Plantas , Infertilidade das Plantas/genética , Brassica rapa/genética , Proteínas de Plantas/genética , Genes de Plantas , Ligação Genética , Mutação
7.
Int J Mol Sci ; 25(10)2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38791166

RESUMO

Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.


Assuntos
Ataxias Espinocerebelares , Humanos , Feminino , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/congênito , Proteínas de Transporte Vesicular/genética , Adulto , Fenótipo , Mutação , Genes Recessivos , Linhagem , Proteínas
9.
PLoS One ; 19(5): e0302991, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722855

RESUMO

Recessive dystrophic epidermolysis bullosa is a rare genodermatosis caused by a mutation of the Col7a1 gene. The Col7a1 gene codes for collagen type VII protein, a major component of anchoring fibrils. Mutations of the Col7a1 gene can cause aberrant collagen type VII formation, causing an associated lack or absence of anchoring fibrils. This presents clinically as chronic blistering, scarring, and fibrosis, often leading to the development of cutaneous squamous cell carcinoma. Patients also experience persistent pain and pruritus. Pain management and supportive bandaging remain the primary treatment options. The pathology of recessive dystrophic epidermolysis bullosa was first described in the 1980s, and there has since been a multitude of encouraging treatment options developed. However, in vivo research has been hindered by inadequate models of the disease. The various mouse models in existence possess longevity and surface area constraints, or do not adequately model a normal human disease state. In this paper, we describe a novel rat model of recessive dystrophic epidermolysis bullosa that offers an alternative to previous murine models. An 8-base pair deletion was induced in the Col7a1 gene of Lewis rats, which was subsequently found to cause a premature stop codon downstream. Homozygous mutants presented with a fragile and chronically blistered phenotype postnatally. Further histological analysis revealed subepidermal clefting and the absence of anchoring fibrils. The generation of this novel model offers researchers an easily maintained organism that possesses a larger surface area for experimental topical and transfused therapies to be tested, which may provide great utility in the future study of this debilitating disease.


Assuntos
Colágeno Tipo VII , Modelos Animais de Doenças , Epidermólise Bolhosa Distrófica , Mutação da Fase de Leitura , Fenótipo , Colágeno Tipo VII/genética , Animais , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Ratos , Genes Recessivos , Ratos Endogâmicos Lew , Vesícula/genética , Vesícula/patologia , Pele/patologia , Masculino
10.
PeerJ ; 12: e17438, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38818455

RESUMO

Background: The identification and analysis of allelic variation are important bases for crop diversity research, trait domestication and molecular marker development. Grain tannin content is a very important quality trait in sorghum. Higher tannin levels in sorghum grains are usually required when breeding varieties resistant to bird damage or those used for brewing liquor. Non-tannin-producing or low-tannin-producing sorghum accessions are commonly used for food and forage. Tan1 and Tan2, two important cloned genes, regulate tannin biosynthesis in sorghum, and mutations in one or two genes will result in low or no tannin content in sorghum grains. Even if sorghum accessions contain dominant Tan1 and Tan2, the tannin contents are distributed from low to high, and there must be other new alleles of the known regulatory genes or new unknown genes contributing to tannin production. Methods: The two parents 8R306 and 8R191 did not have any known recessive alleles for Tan1 and Tan2, and it was speculated that they probably both had dominant Tan1 and Tan2 genotypes. However, the phenotypes of two parents were different; 8R306 had tannins and 8R191 had non-tannins in the grains, so these two parents were constructed as a RIL population. Bulked segregant analysis (BSA) was used to determine other new alleles of Tan1 and Tan2 or new Tannin locus. Tan1 and Tan2 full-length sequences and tannin contents were detected in wild sorghum resources, landraces and cultivars. Results: We identified two novel recessive tan1-d and tan1-e alleles and four recessive Tan2 alleles, named as tan2-d, tan2-e, tan2-f, and tan2-g. These recessive alleles led to loss of function of Tan1 and Tan2, and low or no tannin content in sorghum grains. The loss-of-function alleles of tan1-e and tan2-e were only found in Chinese landraces, and other alleles were found in landraces and cultivars grown all around the world. tan1-a and tan1-b were detected in foreign landraces, Chinese cultivars and foreign cultivars, but not in Chinese landraces. Conclusion: These results implied that Tan1 and Tan2 recessive alleles had different geographically distribution in the worldwide, but not all recessive alleles had been used in breeding. The discovery of these new alleles provided new germplasm resources for breeding sorghum cultivars for food and feed, and for developing molecular markers for low-tannin or non-tannin cultivar-assisted breeding in sorghum.


Assuntos
Alelos , Sorghum , Taninos , Sorghum/genética , Sorghum/metabolismo , Taninos/metabolismo , Taninos/análise , Genes Recessivos/genética , Genes de Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fenótipo
11.
Hum Immunol ; 85(3): 110805, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38703415

RESUMO

Epidermolysis bullosa (EB) is an umbrella term for a group of rare inherited skin disorders characterised by mucocutaneous fragility. Patients suffer from blisters and chronic wounds that arise spontaneously or following minor mechanical trauma, often resulting in inflammation, scarring and fibrosis due to poor healing. The recessive form of dystrophic EB (RDEB) has a particularly severe phenotype and is caused by mutations in the COL7A1 gene, encoding the collagen VII protein, which is responsible for adhering the epidermis and dermis together. One of the most feared and devastating complications of RDEB is the development of an aggressive form of cutaneous squamous cell carcinoma (cSCC), which is the main cause of mortality in this patient group. However, pathological drivers behind the development and progression of RDEB-associated cSCC (RDEB-cSCC) remain somewhat of an enigma, and the evidence to date points towards a complex process. Currently, there is no cure for RDEB-cSCC, and treatments primarily focus on prevention, symptom management and support. Therefore, there is an urgent need for a comprehensive understanding of this cancer's pathogenesis, with the aim of facilitating the discovery of drug targets. This review explores the current knowledge of RDEB-cSCC, emphasising the important role of the immune system, genetics, fibrosis, and the tumour-promoting microenvironment, all ultimately intricately interconnected.


Assuntos
Carcinoma de Células Escamosas , Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Neoplasias Cutâneas , Humanos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Colágeno Tipo VII/genética , Mutação , Animais , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fibrose , Genes Recessivos
12.
Genes (Basel) ; 15(4)2024 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-38674419

RESUMO

Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies.


Assuntos
Miopatias Distais , Humanos , Miopatias Distais/genética , Miopatias Distais/patologia , Masculino , Feminino , Adulto , República da Coreia , Sequenciamento do Exoma , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Mutação de Sentido Incorreto , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Linhagem , Mutação , Genes Recessivos
13.
Am J Med Genet A ; 194(8): e63617, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38568055

RESUMO

Monoallelic pathogenic HMBS variants are a well-established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS-related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8-year-old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS-related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS-related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms.


Assuntos
Transtornos do Neurodesenvolvimento , Fenótipo , Humanos , Feminino , Criança , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Sequenciamento do Exoma , Mutação/genética , Imageamento por Ressonância Magnética , Genes Recessivos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Leucoencefalopatias/diagnóstico por imagem , Linhagem
14.
J Mol Diagn ; 26(7): 638-651, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38663495

RESUMO

Noninvasive prenatal diagnosis (NIPD) for autosomal recessive nonsyndromic hearing loss (ARNSHL) has been rarely reported until recent years. Additionally, the existing method can not be used for challenging genome loci (eg, copy number variations, deletions, inversions, or gene recombinants) or on families without proband genotype. This study assessed the performance of relative haplotype dosage analysis (RHDO)-based NIPD for identifying fetal genotyping in pregnancies at risk of ARNSHL. Fifty couples carrying pathogenic variants associated with ARNSHL in either GJB2 or SLC26A4 were recruited. The RHDO-based targeted linked-read sequencing combined with whole gene coverage probes was used to genotype the fetal cell-free DNA of 49 families who met the quality control standard. Fetal amniocyte samples were genotyped using invasive prenatal diagnosis (IPD) to assess the performance of NIPD. The NIPD results showed 100% (49/49) concordance with those obtained through IPD. Two families with copy number variation and recombination were also successfully identified. Sufficient specific informative single-nucleotide polymorphisms for haplotyping, as well as the fetal cell-free DNA concentration and sequencing depth, are prerequisites for RHDO-based NIPD. This method has the merits of covering the entire genes of GJB2 and SLC26A4, qualifying for copy number variation and recombination analysis with remarkable sensitivity and specificity. Therefore, it has clinical potential as an alternative to traditional IPD for ARNSHL.


Assuntos
Alelos , Conexina 26 , Haplótipos , Transportadores de Sulfato , Humanos , Transportadores de Sulfato/genética , Feminino , Gravidez , Polimorfismo de Nucleotídeo Único , Teste Pré-Natal não Invasivo/métodos , Conexinas/genética , Diagnóstico Pré-Natal/métodos , Variações do Número de Cópias de DNA , Surdez/genética , Surdez/diagnóstico , Genótipo , Masculino , Genes Recessivos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Membrana Transportadoras/genética
15.
Eur J Hum Genet ; 32(7): 837-845, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38658779

RESUMO

Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and cancer phenotypes. Through the analysis of mutational patterns of patient-derived fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons, we concluded that heterozygous POLD1 L474P just subtly increases the somatic and germline mutation burden. In contrast, tumors developed in individuals with a heterozygous mutation in the exonuclease domain of POLD1, including L474P, have an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d. We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.


Assuntos
DNA Polimerase III , Humanos , DNA Polimerase III/genética , DNA Polimerase III/metabolismo , Feminino , Masculino , Linhagem , Heterozigoto , Genes Recessivos , Neoplasias/genética , Neoplasias/patologia , Mutação , Mutação em Linhagem Germinativa , Adulto
16.
Theor Appl Genet ; 137(5): 114, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38678513

RESUMO

KEY MESSAGE: Map-based cloning revealed that a mutation in a highly conserved amino acid of the CsGME gene encoding GDP-mannose 3,5-epimerase, causes the phenotype of little and wrinkled leaves in cucumbers. Leaf size is a critical determinant of plant architecture in cucumbers, yet only a few genes associated with this trait have been mapped or cloned. Here, we identified and characterized a mutant with little and wrinkled leaves, named lwl-1. Genetic analysis revealed that the phenotype of the lwl-1 was controlled by a single recessive gene. Through map-based cloning, the lwl-1 locus was narrowed down to a 12.22-kb region exclusively containing one fully annotated gene CsGME (CsaV3_2G004170). CsGME encodes GDP-mannose 3,5-epimerase, which is involved in the synthesis of ascorbic acid (ASA) and one of the components of pectin, RG-II. Whole-length sequencing of the 12.22 kb DNA fragment revealed the presence of only a non-synonymous mutation located in the sixth exon of CsGME in lwl-1, resulting in an amino acid alteration from Pro363 to Leu363. This mutation was unique among 118 inbred lines from cucumber natural populations. CsGME expression significantly reduced in various organs of lwl-1, accompanied by a significant decrease in ASA and pectin content in leaves. Both CsGME and Csgme proteins were localized to the cytoplasm. The mutant phenotype exhibited partial recovery after the application of exogenous boric acid. Silencing CsGME in cucumber through VIGS confirmed its role as the causal gene for lwl-1. Transcriptome profiling revealed that CsGME greatly affected the expression of genes related to the cell division process and cell plate formation. This study represents the first report to characterize and clone the CsGME in cucumber, indicating its crucial role in regulating leaf size and development.


Assuntos
Carboidratos Epimerases , Mapeamento Cromossômico , Cucumis sativus , Folhas de Planta , Ácido Ascórbico/metabolismo , Carboidratos Epimerases/genética , Carboidratos Epimerases/metabolismo , Clonagem Molecular , Cucumis sativus/genética , Cucumis sativus/crescimento & desenvolvimento , Cucumis sativus/enzimologia , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Genes Recessivos , Mutação , Fenótipo , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
17.
Hum Genomics ; 18(1): 35, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570878

RESUMO

BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.


Assuntos
Degenerações Espinocerebelares , Criança , Humanos , Irã (Geográfico)/epidemiologia , Degenerações Espinocerebelares/genética , Testes Genéticos , Fenótipo , Genes Recessivos
18.
Exp Dermatol ; 33(4): e15072, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38576105

RESUMO

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).


Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Humanos , Ictiose Lamelar/genética , Ictiose Lamelar/patologia , DNA Complementar , Genes Recessivos , Mutação , Ictiose/genética , Eritrodermia Ictiosiforme Congênita/genética , Estudos de Associação Genética , Transportadores de Cassetes de Ligação de ATP/genética
19.
Theor Appl Genet ; 137(4): 92, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38568320

RESUMO

KEY MESSAGE: A chromosome fragment influencing wheat heading and grain size was identified using mapping of m406 mutant. The study of TaFPF1 in this fragment provides more insights into wheat yield improvement. In recent years, wheat production has faced formidable challenges driven by rapid population growth and climate change, emphasizing the importance of improving specific agronomic traits such as heading date, spike length, and grain size. To identify potential genes for improving these traits, we screened a wheat EMS mutant library and identified a mutant, designated m406, which exhibited a significantly delayed heading date compared to the wild-type. Intriguingly, the mutant also displayed significantly longer spike and larger grain size. Genetic analysis revealed that a single recessive gene was responsible for the delayed heading. Surprisingly, a large 46.58 Mb deletion at the terminal region of chromosome arm 2DS in the mutant was identified through fine mapping and fluorescence in situ hybridization. Thus, the phenotypes of the mutant m406 are controlled by a group of linked genes. This deletion encompassed 917 annotated high-confidence genes, including the previously studied wheat genes Ppd1 and TaDA1, which could affect heading date and grain size. Multiple genes in this region probably contribute to the phenotypes of m406. We further investigated the function of TaFPF1 using gene editing. TaFPF1 knockout mutants showed delayed heading and increased grain size. Moreover, we identified the direct upstream gene of TaFPF1 and investigated its relationship with other important flowering genes. Our study not only identified more genes affecting heading and grain development within this deleted region but also highlighted the potential of combining these genes for improvement of wheat traits.


Assuntos
Agricultura , Triticum , Triticum/genética , Hibridização in Situ Fluorescente , Genes Recessivos , Grão Comestível , Cromossomos
20.
BMC Genomics ; 25(1): 417, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38678201

RESUMO

BACKGROUND: Between 2020 and 2022, eight calves in a Nebraska herd (composite Simmental, Red Angus, Gelbvieh) displayed exercise intolerance during forced activity. In some cases, the calves collapsed and did not recover. Available sire pedigrees contained a paternal ancestor within 2-4 generations in all affected calves. Pedigrees of the calves' dams were unavailable, however, the cows were ranch-raised and retained from prior breeding seasons, where bulls used for breeding occasionally had a common ancestor. Therefore, it was hypothesized that a de novo autosomal recessive variant was causative of exercise intolerance in these calves. RESULTS: A genome-wide association analysis utilizing SNP data from 6 affected calves and 715 herd mates, followed by whole-genome sequencing of 2 affected calves led to the identification of a variant in the gene PYGM (BTA29:g.42989581G > A). The variant, confirmed to be present in the skeletal muscle transcriptome, was predicted to produce a premature stop codon (p.Arg650*). The protein product of PYGM, myophosphorylase, breaks down glycogen in skeletal muscle. Glycogen concentrations were fluorometrically assayed as glucose residues demonstrating significantly elevated glycogen concentrations in affected calves compared to cattle carrying the variant and to wild-type controls. The absence of the PYGM protein product in skeletal muscle was confirmed by immunohistochemistry and label-free quantitative proteomics analysis; muscle degeneration was confirmed in biopsy and necropsy samples. Elevated skeletal muscle glycogen persisted after harvest, resulting in a high pH and dark-cutting beef, which is negatively perceived by consumers and results in an economic loss to the industry. Carriers of the variant did not exhibit differences in meat quality or any measures of animal well-being. CONCLUSIONS: Myophosphorylase deficiency poses welfare concerns for affected animals and negatively impacts the final product. The association of the recessive genotype with dark-cutting beef further demonstrates the importance of genetics to not only animal health but to the quality of their product. Although cattle heterozygous for the variant may not immediately affect the beef industry, identifying carriers will enable selection and breeding strategies to prevent the production of affected calves.


Assuntos
Estudo de Associação Genômica Ampla , Glicogênio Fosforilase Muscular , Animais , Bovinos , Feminino , Masculino , Doenças dos Bovinos/genética , Genes Recessivos , Glicogênio Fosforilase Muscular/genética , Glicogênio Fosforilase Muscular/deficiência , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
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