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PLoS Biology Sep 2023Optogenetic actuators have revolutionized the resolution at which biological processes can be controlled. In plants, deployment of optogenetics is challenging due to the...
Optogenetic actuators have revolutionized the resolution at which biological processes can be controlled. In plants, deployment of optogenetics is challenging due to the need for these light-responsive systems to function in the context of horticultural light environments. Furthermore, many available optogenetic actuators are based on plant photoreceptors that might crosstalk with endogenous signaling processes, while others depend on exogenously supplied cofactors. To overcome such challenges, we have developed Highlighter, a synthetic, light-gated gene expression system tailored for in planta function. Highlighter is based on the photoswitchable CcaS-CcaR system from cyanobacteria and is repurposed for plants as a fully genetically encoded system. Analysis of a re-engineered CcaS in Escherichia coli demonstrated green/red photoswitching with phytochromobilin, a chromophore endogenous to plants, but also revealed a blue light response likely derived from a flavin-binding LOV-like domain. We deployed Highlighter in transiently transformed Nicotiana benthamiana for optogenetic control of fluorescent protein expression. Using light to guide differential fluorescent protein expression in nuclei of neighboring cells, we demonstrate unprecedented spatiotemporal control of target gene expression. We implemented the system to demonstrate optogenetic control over plant immunity and pigment production through modulation of the spectral composition of broadband visible (white) light. Highlighter is a step forward for optogenetics in plants and a technology for high-resolution gene induction that will advance fundamental plant biology and provide new opportunities for crop improvement.
Topics: Optogenetics; Nicotiana; Arachnodactyly; Escherichia coli; Gene Expression
PubMed: 37733664
DOI: 10.1371/journal.pbio.3002303 -
Genetics in Medicine : Official Journal... Jun 2021The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we...
PURPOSE
The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.
METHODS
Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.
RESULTS
A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.
CONCLUSION
We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.
Topics: Child; Developmental Disabilities; Frameshift Mutation; Homozygote; Humans; Intellectual Disability; Membrane Proteins; Pedigree; Phenotype; Seizures
PubMed: 33531666
DOI: 10.1038/s41436-021-01097-x -
The Application of Clinical Genetics 2022Meier-Gorlin syndrome (MGS) is a rare genetic syndrome inherited in an autosomal dominant or autosomal recessive manner. The disorder is characterized by bilateral...
BACKGROUND
Meier-Gorlin syndrome (MGS) is a rare genetic syndrome inherited in an autosomal dominant or autosomal recessive manner. The disorder is characterized by bilateral microtia, absence or hypoplasia of the patella, and an intrauterine growth retardation as well as a number of other characteristic features. The cause of the disease is mutations in genes encoding proteins involved in the regulation of the cell cycle (, and ). Meier-Gorlin syndrome 5 due to mutations in the gene is difficult to diagnose, and few clinical data have been described to date. Only one patient (male) with a missense mutation in a homozygous state has been previously reported. This report describes a new clinical case of Meier-Gorlin syndrome 5. This is also the first report of a Russian patient with Meier-Gorlin syndrome.
CASE PRESENTATION
The patient, a female, had extremely low physical development, neonatal progeroid appearance, lipodystrophy, thin skin, partial alopecia, cyanosis of the face, triangular face, microgenia, arachnodactyly, delayed bone age, hepatomegaly, hypoplasia of the labia majora, and hypertrophy of the clitoris in addition to known clinical signs. Differential diagnosis was performed with chromosomal abnormalities and Hutchinson-Gilford progeria. According to the results of sequencing of the clinical exome, the patient had two previously undescribed variants in the gene, c.230A>G (p.(Lys77Arg)) and c.232C>T (p.(Gln78Ter)), NM_001254.3, in a compound heterozygous state.
CONCLUSION
This case allows us to learn more about the clinical features and nature of MGS 5 and improve the speed of diagnostics and quality of genetic counseling for such families.
PubMed: 35023948
DOI: 10.2147/TACG.S342804 -
Movement Disorders : Official Journal... Jul 2020
Topics: Arachnodactyly; Child; Chromosome Deletion; Craniosynostoses; DiGeorge Syndrome; Humans; Movement Disorders; Phenotype
PubMed: 32379361
DOI: 10.1002/mds.28078 -
Quantitative Imaging in Medicine and... May 2023
PubMed: 37179920
DOI: 10.21037/qims-22-806 -
Human Genome Variation Feb 2024Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and...
Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and crumpled ears. We report a case of a boy with suspected Marfan syndrome. Genetic analysis revealed c.3207_3217+9del in a heterozygote form of the fibrillin-2 (FBN2) gene. This patient was diagnosed with CCA based on his phenotype, and the pathogenicity of this variant was classified according to cDNA analysis and protein modeling.
PubMed: 38326314
DOI: 10.1038/s41439-024-00264-1 -
Stem Cell Research Oct 2019The human induced pluripotent stem cell line HELPi001-A was derived from peripheral blood mononuclear cells (PBMC) of a 35-year-old female Beals syndrome patient...
The human induced pluripotent stem cell line HELPi001-A was derived from peripheral blood mononuclear cells (PBMC) of a 35-year-old female Beals syndrome patient carrying a heterozygous FBN2c.728 T > C mutation. HELPi001-A were positive for pluripotent stem cell markers, had a normal karyotype and the ability to differentiate into cells representing all three germ layers. The patient not only demonstrated typical characteristics of Beals syndrome such as joint contractures and crumpled ears, but also demonstrated aortic dissection. HELPi001-A could serve as a platform for exploring the pathogenesis of cardiovascular and connective tissue disorders related to FBN2 mutation.
Topics: Adult; Arachnodactyly; Cell Differentiation; Cell Line; Contracture; Female; Fibrillin-2; Heterozygote; Humans; Induced Pluripotent Stem Cells; Karyotype; Leukocytes, Mononuclear; Polymorphism, Single Nucleotide
PubMed: 31426022
DOI: 10.1016/j.scr.2019.101535 -
Cureus Jul 2021Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder that has several phenotypic similarities to Marfan syndrome. Among the phenotypic...
Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder that has several phenotypic similarities to Marfan syndrome. Among the phenotypic characteristics of patients with CCA, severe kyphoscoliosis and thoracic cage abnormalities are commonly reported. In this case report, we describe a patient with coexisting CCA and severe pectus excavatum requiring multiple surgical repairs. The impact severe scoliosis and pectus excavatum in isolation have on cardiopulmonary anatomy and physiology can be significant, and their effects can be profound concomitantly. These defects have the propensity of causing restrictive lung disease and external cardiac compression.
PubMed: 34466327
DOI: 10.7759/cureus.16701 -
International Journal of Molecular... May 2024Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of...
Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.
Topics: Humans; Fibrillin-1; Marfan Syndrome; Fibrillin-2; Male; Infant, Newborn; Heart Defects, Congenital; High-Throughput Nucleotide Sequencing; Female; Polymorphism, Single Nucleotide; Mutation; Genomics; Phenotype; Exome Sequencing; Adipokines
PubMed: 38791509
DOI: 10.3390/ijms25105469 -
Molecular Genetics & Genomic Medicine Aug 201922q11 deletion syndrome (22qDS) is caused by deletion of chromosome region 22q11.2. However, mosaic cases with 22q11.2 deletion syndrome (22q11.2DS) are rarely reported.
BACKGROUND
22q11 deletion syndrome (22qDS) is caused by deletion of chromosome region 22q11.2. However, mosaic cases with 22q11.2 deletion syndrome (22q11.2DS) are rarely reported.
METHODS
Chromosomal microarray analysis (CMA) and fluorescence in situ hybridization fluorescence in situ hybridization (FISH) were performed to analyze the copy number alterations. Clinical examinations related to 22q11.2DS were performed on the carrier in this family.
RESULTS
A healthy female in a Chinese family with a history of two pregnancies with conotruncal defects, one with pulmonary atresia (PA) and another with Tetralogy of Fallot (TOF) was recruited in this study. CMA revealed that the fetus with TOF has a microdeletion on the 22q11.2 locus, and his mother was further confirmed a somatic mosaicism of 22q11.2 microdeletion by interphase FISH. Somatic mosaic 22q11.2 deletion in the mother was validated in the metaphase lymphocytes. Clinical examinations related to 22q11.2DS showed that the mother had hypocalcemia and low percentages of CD4 + T helper cells. The family history of recurrent fetal conotruncal defects and genetic results demonstrated the inherited possibility of maternal germline mosaicism of the 22q11.2 microdeletion.
CONCLUSION
Our report was the first case in a Chinese family to present that a somatic and suspected gonadal mosaicism of the 22q11.2 microdeletion in female causes recurrent fetal conotruncal defects.
Topics: Adult; Arachnodactyly; Craniosynostoses; DiGeorge Syndrome; Female; Fetus; Gene Dosage; Humans; In Situ Hybridization, Fluorescence; Marfan Syndrome; Medical History Taking; Mosaicism; Pedigree; Pregnancy; Prenatal Diagnosis; Pulmonary Atresia; Tetralogy of Fallot
PubMed: 31297990
DOI: 10.1002/mgg3.847