Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20.094
Filtrar
1.
Am J Hum Genet ; 108(11): 2130-2144, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34653363

RESUMO

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Genes Dominantes , Hexosiltransferases/genética , Proteínas de Membrana/genética , Doenças Musculoesqueléticas/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Sequência de Aminoácidos , Domínio Catalítico , Pré-Escolar , Feminino , Heterozigoto , Hexosiltransferases/química , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Linhagem , Homologia de Sequência de Aminoácidos
3.
Science ; 373(6559): 1156-1161, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34516839
4.
Eur J Med Genet ; 64(10): 104311, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34416374

RESUMO

Hereditary hearing loss (HL) has high genetic and phenotypical heterogeneity including the overlapping and variable phenotypic features. For sporadic HL without a family history, it is more difficult to indicate the contribution of genetic factors to define a pattern of inheritance. We assessed the contribution of genetic variants and patterns of inheritance by a family trio-based sequencing and provided new insight into genetics. We conducted an analysis of data from unrelated sporadic patients with HL (n = 404) who underwent trio-based whole-exome sequencing (trio-WES) or proband-only WES (p-WES) or targeted exome sequencing (TES), and the samples of their unaffected-parents (n = 808)were validated. A molecular diagnosis was rendered for 191 of 404 sporadic HL patients (47.3%) in multiple modes of inheritance, including autosomal recessive (AR), autosomal dominant (AD) caused by de novo variants, copy-number variants (CNVs), X-linked recessive, and dual genetic diagnosis. Among these patients, 83 (43.5%) cases were diagnosed with variants in rare genes. Sporadic HL patients were identified by multiple modes of transmission. Observed variations in rare genes and multiple modes of inheritance can strikingly emphasize the important etiological contribution of recessive and de novo genetic variants to a large cohort of sporadic HL cases plus their parents.


Assuntos
Genes Recessivos , Perda Auditiva Neurossensorial/genética , Mutação , Adolescente , Adulto , Variações do Número de Cópias de DNA , Feminino , Frequência do Gene , Genes Dominantes , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Linhagem
5.
Anim Genet ; 52(5): 749-753, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34403536

RESUMO

The dominance effect is a kind of non-additive effect due to the interaction between alleles at the same locus. Quantitative traits such as growth traits in farm animals have been found to be influenced by dominance effects. However, dominance effects are usually ignored in the genome-wide association study (GWAS) of complex traits for farm animals. In this study, we performed GWAS and genetic parameters estimation for the two traits age at 100 kg (AGE) and backfat thickness at 100 kg (BF) of 3572 Large White pigs. The pigs were from three breeding farms of China and were genotyped by an in-house designed 50k SNP chip. Our results showed significant non-zero variance for the dominance effect of AGE, while the dominance effect of BF was not significant. Using a GWAS model accounting for both additive and dominance effects, we identified three additive and two dominance significant SNPs for the trait AGE. For the trait BF, three genome-wide significant additive SNPs were detected, but no significant SNP was found for the dominance effect. In total, six important functional genes (NPAS3, USP16, PARN, ARL15, GPC3, ABHD4) near significant SNPs were identified as candidate genes associated with AGE or BF. Notably, ARL15 and PARN were associated with AGE near the dominance association signals. Overall, the newly detected SNPs and newly identified candidate genes in our study added new information about the genetic architectures of growth and fatness traits in pigs, and have the potential to be applied to the pig breeding program in the future.


Assuntos
Adiposidade/genética , Genes Dominantes , Sus scrofa/crescimento & desenvolvimento , Sus scrofa/genética , Animais , China , Estudos de Associação Genética/veterinária , Genótipo , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único
6.
Theor Appl Genet ; 134(11): 3721-3730, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34379146

RESUMO

KEY MESSAGE: AhRt1 controlling red testa color in peanut was fine-mapped to an interval of 580 kb on chromosome A03, and one gene encoding bHLH transcriptional factor was identified as the putative candidate gene. Peanut with red testa has higher nutritional and economic value than the traditional pink testa varieties. Identification of genes controlling red testa color will accelerate the breeding program and facilitate uncovering the genetic mechanism. In this study, in order to identify gene underlying the red testa color in peanut, a F2 population derived from a cross between a pink testa peanut variety "Fuhua 8" and a red testa variety "Quanhonghua 1" was constructed. The genetic analysis for the F2 population revealed that the red testa color was controlled by one single dominant locus. This locus, named as AhRt1 (Arachis hypogaea Red Testa 1), was preliminary identified in chromosome A03 by BSA-sequencing analysis. Using a segregation mapping population, AhRt1 was fine-mapped to a 580-kb genomic region by substitution mapping strategy. Gene candidate analysis suggested that one predicted gene encoding bHLH transcriptional factor may be the possible candidate gene for AhRt1. A diagnostic marker closely linked to candidate gene has been developed for validating the fine-mapping result in different populations and peanut germplasm. Our findings will benefit the breeding program for developing new varieties with red testa color and laid foundation for map-based cloning gene responsible for red testa in peanut.


Assuntos
Arachis/genética , Genes Dominantes , Genes de Plantas , Pigmentação/genética , Antocianinas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mapeamento Cromossômico , Cor , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único
7.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209661

RESUMO

Self-incompatibility (SI) is conserved among members of the Brassicaceae plant family. This trait is controlled epigenetically by the dominance hierarchy of the male determinant alleles. We previously demonstrated that a single small RNA (sRNA) gene is sufficient to control the linear dominance hierarchy in Brassica rapa and proposed a model in which a homology-based interaction between sRNAs and target sites controls the complicated dominance hierarchy of male SI determinants. In Arabidopsis halleri, male dominance hierarchy is reported to have arisen from multiple networks of sRNA target gains and losses. Despite these findings, it remains unknown whether the molecular mechanism underlying the dominance hierarchy is conserved among Brassicaceae. Here, we identified sRNAs and their target sites that can explain the linear dominance hierarchy of Arabidopsis lyrata, a species closely related to A. halleri. We tested the model that we established in Brassica to explain the linear dominance hierarchy in A. lyrata. Our results suggest that the dominance hierarchy of A. lyrata is also controlled by a homology-based interaction between sRNAs and their targets.


Assuntos
Arabidopsis/genética , Epistasia Genética , Regulação da Expressão Gênica de Plantas , Genes Dominantes , Recombinação Homóloga , RNA de Plantas , Predomínio Social , Alelos , Genótipo , Haplótipos , Conformação de Ácido Nucleico
10.
Nat Genet ; 53(7): 1006-1021, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34211179

RESUMO

SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.


Assuntos
Genes Dominantes , Predisposição Genética para Doença , Variação Genética , Transtornos do Neurodesenvolvimento/genética , Espectrina/genética , Animais , Estudos de Associação Genética/métodos , Heterozigoto , Humanos , Camundongos , Transtornos do Neurodesenvolvimento/diagnóstico , Fenótipo , Espectrina/metabolismo
11.
Genes (Basel) ; 12(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204324

RESUMO

Hemp (Cannabis sativa L.) has recently become an important crop due to the growing market demands for products containing cannabinoids. Unintended cross-pollination of C. sativa crops is one of the most important threats to cannabinoid production and has been shown to reduce cannabinoid yield. Ploidy manipulation has been used in other crops to improve agronomic traits and reduce fertility; however, little is known about the performance of C. sativa polyploids. In this study, colchicine was applied to two proprietary, inbred diploid C. sativa inbred lines, 'TS1-3' and 'P163', to produce the tetraploids 'TS1-3 (4x)' and 'P163 (4x)'. The diploid, triploid, and tetraploid F1 hybrids from 'TS1-3' × 'P163', 'TS1-3 (4x)' × 'P163', and 'TS1-3 (4x)' × 'P163 (4x)' were produced to test their fertilities, crossing compatibilities, and yields. The results indicated a reduction in fertility in the triploids and the tetraploids, relative to their diploid counterparts. When triploids were used as females, seed yields were less than 2% compared to when diploids were used as females; thus, triploids were determined to be female infertile. The triploids resulting from the crosses made herein displayed increases in biomass and inflorescence weight compared to the diploids created from the same parents in a field setting. Statistical increases in cannabinoid concentrations were not observed. Lastly, asymmetric crossing compatibility was observed between the diploids and the tetraploids of the genotypes tested. The results demonstrate the potential benefits of triploid C. sativa cultivars in commercial agriculture.


Assuntos
Canabinoides/metabolismo , Cannabis/genética , Hibridização Genética , Melhoramento Vegetal , Poliploidia , Canabinoides/genética , Cannabis/fisiologia , Genes Dominantes , Infertilidade das Plantas/genética
12.
Biomed Res Int ; 2021: 5574136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34250087

RESUMO

Background: The pathogenic variant, POU class 4 transcription factor 3 (POU4F3), is reported to cause autosomal dominant nonsyndromic hearing loss (ADNSHL). Previously, we have examined a four-generation midfrequency sensorineural hearing loss (MFSNHL) family (no. 6126) and established POU4F3 c.602T>C (p.Leu201Pro) as a potential disease-causing variant. Objectives: We explored the structural and functional alterations that the c.602T>C (p.Leu201Pro) variant enforces on the POU4F3 protein. Methods: We utilized wild-type (WT) and mutant (MUT) POU4F3 c.602T>C plasmid incorporation into HeLa cells to assess functional changes, by immunofluorescence and luciferase assays. To predict protein structural alterations in the MUT versus WT POU4F3, we also generated 3D structures to compare both types of POU4F3 proteins. Results: The WT POU4F3 is ubiquitously present in the nucleus, whereas the MUT form of POU4F3 exhibits a more restricted nuclear presence. This finding is different from other publications, which report a cytoplasmic localization of the MUT POU4F3. We also demonstrated that, as opposed to WT POU4F3, the MUT POU4F3 had 40% reduced luciferase activity. Conclusions: The reduced nuclear presence, combined with reduced transcriptional activity, suggests that the POU4F3 c.602T>C variant alters cellular activity and may contribute to the pathogenicity of POU4F3-related hearing loss. It, also, provides more evidence of the pathophysiological characteristics of MFSNHL.


Assuntos
Núcleo Celular/metabolismo , Genes Dominantes , Perda Auditiva Neurossensorial/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto/genética , Fator de Transcrição Brn-3C/genética , Transcrição Genética , Sequência de Bases , Células HeLa , Proteínas de Homeodomínio/química , Humanos , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Transporte Proteico , Fator de Transcrição Brn-3C/química
13.
Biomed Res Int ; 2021: 6624744, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34258273

RESUMO

Objective: Genetic variants in the WFS1 gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of WFS1 variants. Methods: The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure. Results: A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the WFS1 gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related WFS1 missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein. Conclusions: In this family, we identified a novel variant p.Gly674Trp of WFS1 as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the WFS1 gene.


Assuntos
Retículo Endoplasmático/metabolismo , Genes Dominantes , Perda Auditiva/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Adulto , Idoso de 80 Anos ou mais , Sequência de Bases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Fenótipo
14.
PLoS One ; 16(7): e0254947, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34288964

RESUMO

An additive genetic model is usually employed in case-control-based genome-wide association studies. The model usually encodes "AA", "Aa" and "aa" ("a" represents the minor allele) as three different numbers, implying the contribution of genotype "Aa" to the phenotype is different from "AA" and "aa". From the perspective of biological phenomena, the coding is reasonable since the phenotypes of lives are not "black and white". A case-control based study, however, has only two phenotypes, case and control, which means that the phenotypes are "black and white". It suggests that a recessive/dominant model may be an alternative to the additive model. In order to investigate whether the alternative is feasible, we conducted comparative experiments on several models used in those studies through chi-square test and logistic regression. Our simulation experiments demonstrate that a recessive model is better than the additive model. The area under the curve of the former has increased by 5% compared with the latter, the discrimination of identifying risk single nucleotide polymorphisms has been improved by 61%, and the precision has also reached 1.10 times that of the latter. Furthermore, the real data experiments show that the precision and area under the curve of the former are 16% and 20% higher than the latter respectively, and the area under the curve of dominant model of the former is 13% higher than the latter. The results indicate a recessive/dominant model may be an alternative to the additive model and suggest a new route for case-control-based studies.


Assuntos
Doença da Artéria Coronariana/genética , Bases de Dados de Ácidos Nucleicos , Genes Dominantes , Genes Recessivos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos
15.
Hum Genet ; 140(8): 1183-1200, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34076780

RESUMO

Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.


Assuntos
Dislexia/genética , Predisposição Genética para Doença , Padrões de Herança , Polimorfismo de Nucleotídeo Único , Semaforinas/genética , Sequência de Bases , Movimento Celular , Cromossomos Humanos Par 7 , Dislexia/diagnóstico por imagem , Dislexia/metabolismo , Dislexia/fisiopatologia , Família , Feminino , Expressão Gênica , Genes Dominantes , Ligação Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Íntrons , Escore Lod , Masculino , Neuroimagem , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Fenótipo , Semaforinas/deficiência , Sequenciamento Completo do Genoma
16.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070858

RESUMO

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.


Assuntos
Demência Frontotemporal/genética , Genes Dominantes , Genes Recessivos , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases , Adulto , Idade de Início , Idoso , Família , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Expressão Gênica , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Dobramento de Proteína , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia
17.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071252

RESUMO

Gene-expression programs modulated by transcription factors (TFs) mediate key developmental events. Here, we show that the synthetic transcriptional repressor (TR; ZF6-DB), designed to treat Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP), does not perturb murine retinal development, while maintaining its ability to block Rho expression transcriptionally. To express ZF6-DB into the developing retina, we pursued two approaches, (i) the retinal delivery (somatic expression) of ZF6-DB by Adeno-associated virus (AAV) vector (AAV-ZF6-DB) gene transfer during retinogenesis and (ii) the generation of a transgenic mouse (germ-line transmission, TR-ZF6-DB). Somatic and transgenic expression of ZF6-DB during retinogenesis does not affect retinal function of wild-type mice. The P347S mouse model of RHO-adRP, subretinally injected with AAV-ZF6-DB, or crossed with TR-ZF6-DB or shows retinal morphological and functional recovery. We propose the use of developmental transitions as an effective mode to challenge the safety of retinal gene therapies operating at genome, transcriptional, and transcript levels.


Assuntos
Terapia Genética/métodos , Retina/metabolismo , Retinite Pigmentosa/genética , Animais , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Expressão Gênica , Genes Dominantes , Vetores Genéticos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Retinite Pigmentosa/metabolismo , Rodopsina/genética , Fatores de Transcrição , Transcriptoma , Dedos de Zinco
18.
Nat Med ; 27(7): 1197-1204, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059824

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Esfingolipídeos/biossíntese , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Esclerose Amiotrófica Lateral/enzimologia , Esclerose Amiotrófica Lateral/genética , Sistemas CRISPR-Cas , Criança , Feminino , Genes Dominantes , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo , Adulto Jovem
19.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34137790

RESUMO

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.


Assuntos
Genes Dominantes , Síndrome de Job/genética , Mutação/genética , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Alelos , Processamento Alternativo/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Evolução Molecular , Família , Feminino , Mutação da Fase de Leitura/genética , Genética Populacional , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
Am J Hum Genet ; 108(6): 1040-1052, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33964207

RESUMO

SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane protein required for transporting glucose-6-phosphate (Glc-6P) into the ER. Once transported into the ER, Glc-6P is subsequently hydrolyzed by tissue-specific phosphatases to glucose and inorganic phosphate during times of glucose depletion. Pathogenic variants in SLC37A4 cause an established recessive disorder known as glycogen storage disorder 1b characterized by liver and kidney dysfunction with neutropenia. We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423∗), in SLC37A4; the affected individuals were from four unrelated families. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans, while N-glycans in fibroblasts and undifferentiated iPSC were normal. Due to the liver-specific nature of this disorder, we generated a CRISPR base-edited hepatoma cell line harboring the c.1267C>T (p.Arg423∗) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.


Assuntos
Antiporters/genética , Defeitos Congênitos da Glicosilação/etiologia , Retículo Endoplasmático/patologia , Hepatopatias/complicações , Proteínas de Transporte de Monossacarídeos/genética , Mutação , Adulto , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/patologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Genes Dominantes , Glicosilação , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...