-
Cell Reports Mar 2015Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an...
Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2 mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.
PubMed: 25753423
DOI: 10.1016/j.celrep.2015.02.011 -
Military Medicine Oct 2022The submarine environment presents unique challenges in mitigating the spread of respiratory viruses because of the re-circulatory atmosphere and lack of ability to...
BACKGROUND
The submarine environment presents unique challenges in mitigating the spread of respiratory viruses because of the re-circulatory atmosphere and lack of ability to physically distance. The atmosphere of a submarine is periodically ventilated and continuously scrubbed. However, the air is recycled for months until the ship is able to ventilate. An outbreak of coronavirus disease 2019 (COVID-19) occurred on a U.S. Navy fast-attack nuclear submarine (SSN) with a crew of 128 personnel.
METHODS
Demographics, symptom data, and test results for all crew members on board during the outbreak were collected. Testing was completed by real-time reverse-transcriptase polymerase chain reaction, and symptom data were collected via a patient-reported online application. Symptom results were collected from August 4, 2020 to September 1, 2020.
RESULTS
The crew was 100% male, with a mean age of 27.0 years. All crew members met the stringent medical standards for submarine and sea duty. Fifty-five Sailors tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (43.0% of the crew) during the outbreak. Additionally, nine Sailors (7.0% of the crew) met the criteria for infection despite testing negative, resulting in an overall attack rate of 50.0%. Among the 64 crew members with suspected or confirmed COVID-19, 1 (1.6%) was hospitalized. There were no deaths. Out of the 55 positive tests, there were 6 (10.9%) asymptomatic positive cases.
CONCLUSIONS
As expected, SARS-CoV-2 was able to spread rapidly among a submarine crew. In 11 days, the infection spread to 64 total crewmembers out of 128. Outbreaks such as these have played a role in future COVID-19 testing and mitigation protocols that have affected day-to-day operations.
Topics: Male; Humans; Adult; Female; COVID-19; SARS-CoV-2; Ships; COVID-19 Testing; Retrospective Studies; Disease Outbreaks
PubMed: 35762151
DOI: 10.1093/milmed/usac155 -
BMC Medical Genetics Dec 2014DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified...
BACKGROUND
DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated.
METHODS
We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies.
RESULTS
Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC).
CONCLUSIONS
We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.
Topics: Animals; Disease Models, Animal; Female; Genetic Heterogeneity; Humans; Immunologic Deficiency Syndromes; Male; Mice; Mutation; NF-kappa B p52 Subunit; Pedigree; Pituitary Hormones, Anterior; Pro-Opiomelanocortin
PubMed: 25524009
DOI: 10.1186/s12881-014-0139-9 -
BMC Medical Genomics Mar 2022Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax,...
BACKGROUND
Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3.
METHODS
We performed a detailed clinical prenatal sonographic characterization of a foetus with SRTD3. Trio whole-exome sequencing was used to identify causative variants in the family. The identified variants in the families were validated by Sanger sequencing and mass spectrometry. Multiple computational tools were used to predict the harmfulness of the two variants. A minigene splicing assay was carried out to evaluate the impact of the splice-site variant.
RESULTS
We evaluated prenatal sonographic images of the foetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly, and foetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001377.3:c.11483T > G (p.Ile3828Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. The minigene assay findings suggested that c.2106 + 3A > T caused the skipping over exon 14, producing an exon 14 loss in the protein.
CONCLUSION
This study identified a foetus with SRTD3 with situs inversus totalis with mirror-image dextrocardia in a Chinese family, revealing two novel compound heterozygous dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) variants, expanding the phenotypic spectrum of SRTD3. The minigene study of c.2106 + 3A > T was predicted to cause an inframe exclusion of exon 14, which was predicted to have important molecular functions. Our findings strongly supported the use of WES in prenatal diagnosis and helped to understand the correlation of genotype and phenotypes of DYNC2H1. The specific sonographic findings and the molecular diagnosis helped add experience to further our expertise in prenatal counselling for SRTD3.
Topics: Cytoplasmic Dyneins; Dextrocardia; Female; Fetus; Humans; Polydactyly; Pregnancy; Short Rib-Polydactyly Syndrome; Situs Inversus
PubMed: 35277174
DOI: 10.1186/s12920-022-01205-z -
International Journal of Molecular... Mar 2017Radiosensitivity differs in humans and likely among primates. The reasons are not well known. We examined pre-exposure gene expression in baboons ( = 17) who developed...
Radiosensitivity differs in humans and likely among primates. The reasons are not well known. We examined pre-exposure gene expression in baboons ( = 17) who developed haematologic acute radiation syndrome (HARS) without pancytopenia or a more aggravated HARS with pancytopenia after irradiation. We evaluated gene expression in a two stage study design where stage I comprised a whole genome screen for messenger RNAs (mRNA) (microarray) and detection of 667 microRNAs (miRNA) (real-time quantitative polymerase chain reaction (qRT-PCR) platform). Twenty candidate mRNAs and nine miRNAs were selected for validation in stage II (qRT-PCR). None of the mRNA species could be confirmed during the validation step, but six of the nine selected candidate miRNA remained significantly different during validation. In particular, miR-425-5p (receiver operating characteristic = 0.98; = 0.0003) showed nearly complete discrimination between HARS groups with and without pancytopenia. Target gene searches of miR-425-5p identified new potential mRNAs and associated biological processes linked with radiosensitivity. We found that one miRNA species examined in pre-exposure blood samples was associated with HARS characterized by pancytopenia and identified new target mRNAs that might reflect differences in radiosensitivity of irradiated normal tissue.
Topics: Acute Radiation Syndrome; Animals; Disease Models, Animal; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Humans; MicroRNAs; Pancytopenia; Papio; RNA, Messenger; Radiation Tolerance
PubMed: 28257102
DOI: 10.3390/ijms18030541 -
American Journal of Human Genetics Jul 2018Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome...
Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.
Topics: Adult; Female; Heterozygote; Humans; Intellectual Disability; Male; Mutation; Seizures; Exome Sequencing; Wiskott-Aldrich Syndrome Protein Family; Young Adult
PubMed: 29961568
DOI: 10.1016/j.ajhg.2018.06.001 -
Current Biology : CB May 2017Cytoplasmic dynein-2 powers retrograde intraflagellar transport that is essential for cilium formation and maintenance. Inactivation of dynein-2 by mutations in DYNC2H1...
Cytoplasmic dynein-2 powers retrograde intraflagellar transport that is essential for cilium formation and maintenance. Inactivation of dynein-2 by mutations in DYNC2H1 causes skeletal dysplasias, and it remains unclear how the dynein-2 heavy chain moves in cilia. Here, using the genome-editing technique to produce fluorescent dynein-2 heavy chain in Caenorhabditis elegans, we show by high-resolution live microscopy that dynein-2 moves in a surprising way along distinct ciliary domains. Dynein-2 shows triphasic movement in the retrograde direction: dynein-2 accelerates in the ciliary distal region and then moves at maximum velocity and finally decelerates adjacent to the base, which may represent a physical obstacle due to transition zone barriers. By knocking the conserved ciliopathy-related mutations into the C. elegans dynein-2 heavy chain, we find that these mutations reduce its transport speed and frequency. Disruption of the dynein-2 tail domain, light intermediate chain, or intraflagellar transport (IFT)-B complex abolishes dynein-2's ciliary localization, revealing their important roles in ciliary entry of dynein-2. Furthermore, our affinity purification and genetic analyses show that IFT-A subunits IFT-139 and IFT-43 function redundantly to promote dynein-2 motility. These results reveal the molecular regulation of dynein-2 movement in sensory cilia.
Topics: Amino Acid Sequence; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cilia; Dyneins; Flagella; Genomics; Mutation; Protein Subunits; Protein Transport; Sensory Receptor Cells; Sequence Homology
PubMed: 28479320
DOI: 10.1016/j.cub.2017.04.015 -
Frontiers in Molecular Neuroscience 2021TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous...
TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.
PubMed: 35002618
DOI: 10.3389/fnmol.2021.757646 -
Molecular Genetics & Genomic Medicine Dec 2020Skeletal ciliopathies are a group of clinically and genetically heterogeneous disorders with the spectrum of severity spanning from relatively mild to prenatally lethal....
BACKGROUND
Skeletal ciliopathies are a group of clinically and genetically heterogeneous disorders with the spectrum of severity spanning from relatively mild to prenatally lethal. The aim of our study was to identify pathogenic mutations in a Chinese family with two siblings presenting a Short-rib polydactyly syndrome (SRPS)-like phenotype.
METHOD
Karyotyping and NGS-based CNVseq were performed. Obtaining the negative results in karyotyping and CNVseq, whole-exome sequencing (WES) using genomic DNA (gDNA) extracted from the umbilical cord blood of the first fetus was carried out, followed by bioinformation analysis. The candidate pathogenic variants were confirmed by Sanger sequencing in the family.
RESULTS
No chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the affected fetus with SRPS-like phenotype. WES analysis identified two novel compound heterozygous variants in DYNC2LI1, c.358G>T (p.Pro120Ser; NM_001193464), and c.928A>T (p.Lys310Ter; NM_ 001193464). Bioinformatics analysis suggested that c.358G>T (p.Pro120Ser) was likely pathogenic and c.928A>T (p.Lys310Ter) was pathogenic. Sanger sequencing of the two variants in family reveal that c.358G>T was from paternal origin and c.928A>T was from maternal origin, and the second affected fetus had the same compound heterozygous variants in DYNC2LI1. Definitive diagnosis of short-rib thoracic dysplasia 15 with polydactyly (SRTD15) was made in the family.
CONCLUSION
Our results expand the mutational spectrum of DYNC2LI1 in severe skeletal ciliopathies. WES facilitates the accurate prenatal diagnosis of fetal skeletal ciliopathy, and provides helpful information for genetic counseling.
Topics: Adult; Ciliopathies; Cytoplasmic Dyneins; Female; Fetus; Heterozygote; Humans; Male; Point Mutation; Pregnancy; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal; Whole Genome Sequencing
PubMed: 33030252
DOI: 10.1002/mgg3.1524 -
BMC Medical Genetics Apr 2015Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination... (Review)
Review
BACKGROUND
Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination of generalized lymphatic dysplasia (ie. lymphedema and lymphangiectasia), variable intellectual disability and characteristic dysmorphic features. The patient we describe here has a lymphatic dysplasia without intellectual disability or dysmorphism caused by mutation in CCBE1, highlighting the phenotypic variability that can be seen with abnormalities in this gene.
CASE PRESENTATION
Our patient is a 5 week old child of Pakistani descent who presented to our center with generalized edema, ascites, and hypoalbuminemia. She was diagnosed with a protein losing enteropathy secondary to segmental primary intestinal lymphangiectasia. As the generalized edema resolved, it became clear that she had mild persistent lymphedema in her hands and feet. No other abnormalities were noted on examination and development was unremarkable at 27 months of age. Given the suspected genetic etiology and the consanguinity in the family, we used a combination of SNP genotyping and exome sequencing to identify the underlying cause of her disease. We identified several large stretches of homozygosity in the patient that allowed us to sort the variants found in the patient's exome to identify p.C98W in CCBE1 as the likely pathogenic variant.
CONCLUSIONS
CCBE1 mutation analysis should be considered in all patients with unexplained lymphatic dysplasia even without the other features of classic Hennekam syndrome.
Topics: Calcium-Binding Proteins; Consanguinity; Craniofacial Abnormalities; DNA Mutational Analysis; Female; Genital Diseases, Male; Genotype; Humans; Hypoalbuminemia; Infant; Lymphangiectasis, Intestinal; Lymphatic System; Lymphedema; Pakistan; Polydactyly; Polymorphism, Single Nucleotide; Protein-Losing Enteropathies; Tumor Suppressor Proteins
PubMed: 25925991
DOI: 10.1186/s12881-015-0175-0