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Journal of Clinical Immunology May 2024Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1...
Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.
Topics: Child, Preschool; Female; Humans; Infant; Male; Alleles; B-Lymphocytes; Immunologic Deficiency Syndromes; Interferon Type I; Mutation; Phenotype
PubMed: 38773012
DOI: 10.1007/s10875-024-01733-6 -
Ophthalmic Research 2024Weill-Marchesani syndrome (WMS) is a hereditary connective tissue disorder with substantial heterogeneity in clinical features and genetic etiology, so it is essential...
INTRODUCTION
Weill-Marchesani syndrome (WMS) is a hereditary connective tissue disorder with substantial heterogeneity in clinical features and genetic etiology, so it is essential to define the full mutation spectrum for earlier diagnosis. In this study, we report Weill-Marchesani-like syndrome (WMS-like) change to autosomal dominance inheritance caused by novel haplotypic mutations in latent transforming growth factor beta-binding protein 2 (LTBP2).
METHODS
Twenty-five members from a 4-generation Chinese family were recruited from Guangzhou, of whom nine were diagnosed with WMS-like disease, nine were healthy, and seven were of "uncertain" clinical status because of their young age. All members received detailed physical and ocular examinations. Whole-exome sequencing, Sanger sequencing, and real-time PCR were used to identify and verify the causative mutations in family members.
RESULTS
Genetic sequencing revealed novel haplotypic mutations on the same LTBP2 chromosome associated with WMS-like, c. 2657C>A/p.T886K in exon 16 and deletion of exons 25-36. Real-time PCR and Sanger sequencing verified both mutations in patients with clinically diagnosed WMS-like, and in one "uncertain" child. In these patients, the haplotypic mutations led to ectopia lentis, short stature, and obesity.
CONCLUSION
Our study revealed that WMS-like may be associated with haplotypic LTBP2 mutations with autosomal dominant inheritance.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Young Adult; China; DNA Mutational Analysis; East Asian People; Exome Sequencing; Haplotypes; Latent TGF-beta Binding Proteins; Mutation; Pedigree; Real-Time Polymerase Chain Reaction; Weill-Marchesani Syndrome
PubMed: 38772353
DOI: 10.1159/000538844 -
Molecular Biology and Evolution Jun 2024High mountains harbor a considerable proportion of biodiversity, but we know little about how diverse plants adapt to the harsh environment. Here we finished a...
High mountains harbor a considerable proportion of biodiversity, but we know little about how diverse plants adapt to the harsh environment. Here we finished a high-quality genome assembly for Dasiphora fruticosa, an ecologically important plant distributed in the Qinghai-Tibetan Plateau and lowland of the Northern Hemisphere, and resequenced 592 natural individuals to address how this horticulture plant adapts to highland. Demographic analysis revealed D. fruticosa underwent a bottleneck after Naynayxungla Glaciation. Selective sweep analysis of two pairs of lowland and highland populations identified 63 shared genes related to cell wall organization or biogenesis, cellular component organization, and dwarfism, suggesting parallel adaptation to highland habitats. Most importantly, we found that stronger purging of estimated genetic load due to inbreeding in highland populations apparently contributed to their adaptation to the highest mountain. Our results revealed how plants could tolerate the extreme plateau, which could provide potential insights for species conservation and crop breeding.
Topics: Selection, Genetic; Genome, Plant; Adaptation, Physiological; Altitude
PubMed: 38768215
DOI: 10.1093/molbev/msae099 -
Frontiers in Microbiology 2024There are three major categories of waterfowl parvoviruses, namely goose parvovirus (GPV), Muscovy duck parvovirus, and novel goose parvovirus (NGPV). NGPV can infect...
INTRODUCTION
There are three major categories of waterfowl parvoviruses, namely goose parvovirus (GPV), Muscovy duck parvovirus, and novel goose parvovirus (NGPV). NGPV can infect both Cherry Valley ducks and mule ducks, resulting in short beaks and dwarfism syndrome, and the incidence of short beaks and dwarfism syndrome rises annually, posing a significant threat to the waterfowl breeding and the animal husbandry. Therefore, clarifying the biological characteristics and genetic evolution of NGPV is very important for the prevention and control of NGPV.
METHODS
Ducks with short beaks and dwarfism syndrome from Shandong and Henan Province were investigated by dissection and the tissue samples were collected for study. The NGPV genome was amplified by PCR, and the genome was analyzed for genetic evolution.
RESULTS
Eight strains of NGPV were isolated, which were designated as HZ0512, HZ0527, HZ0714, HZ0723, HZ0726, HZ0811, HZ0815, and HN0403. The nucleotide homology among these strains ranged from 99.9% to 100%. The eight strains, along with other NGPVs, belong to GPV. The eight strains showed a 92.5%-98.9% nucleotide homology with the classical GPV, while a 96.0%-99.9% homology with NGPV.Therefore, it can be deduced that there have been no major mutations of NGPV in Shandong and Henan provinces in recent years.
DISCUSSION
This study lays a theoretical foundation for further studying the genetic evolution and pathogenicity of NGPV, thereby facilitating the prevention and control of NGPV.
PubMed: 38765684
DOI: 10.3389/fmicb.2024.1373601 -
The Plant Genome Jun 2024Dwarfism is a useful trait in many crop plants because it contributes to improved lodging resistance and harvest index. The mutant allele dw-ref (dwarf-reference) of...
Dwarfism is a useful trait in many crop plants because it contributes to improved lodging resistance and harvest index. The mutant allele dw-ref (dwarf-reference) of sorghum [Sorghum bicolor (L.) Moench] is characterized by an 882 bp tandem duplication in the fifth exon of the gene that is unstable and reverts to wild-type at a frequency greater than 0.001 in many genetic backgrounds. The goal of this research was to identify stable alleles of dw (dwarf3) that could be backcrossed into elite parent lines to improve height stability of the crop. To discover new alleles of dw, a panel consisting mostly of sorghum conversion lines (SC-lines) was screened by polymerase chain reaction for the 882 bp tandem duplication in the fifth exon of dw-ref. Sanger sequencing was used to characterize the DNA sequence of this fragment in genotypes that did not contain the 882 bp tandem duplication. Sequence analysis identified three indel mutations, including an 82 bp deletion, a 6 bp duplication, and a 15 bp deletion in this region of the gene. Field trials of the donor genotypes with these new alleles indicated no wild-type revertants of dw-sd3 (dwarf-stable dwarf), dw-sd4, and dw-sd5. These alleles were backcrossed into Tx430. Field trials of backcross progeny (BCF) with the dw-sd3, dw-sd4, and dw-sd5 alleles indicated no revertants. The plant height and flowering time characteristics of the backcross progeny were similar or slightly shorter and earlier than the recurrent parent. These findings demonstrate that dw-sd3, dw-sd4, and dw-sd5 alleles will be useful in breeding for the stable dwarf trait.
Topics: Sorghum; Alleles; Mutation; Genes, Plant; Plant Proteins; Genotype
PubMed: 38764298
DOI: 10.1002/tpg2.20466 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jun 2024
Topics: Child; Humans; Male; Body Height; Developmental Disabilities; Dwarfism; Forkhead Transcription Factors; Growth Disorders; Heterozygote; Language Development Disorders; Mutation; Phenotype; Syndrome
PubMed: 38763881
DOI: 10.3760/cma.j.cn112140-20231117-00379 -
Plant Physiology and Biochemistry : PPB Jul 2024Apple (Malus domestica Borkh.) is a widely cultivated fruit crop worldwide but often suffers from abiotic stresses such as salt and cold. Gibberellic acid (GA) plays a...
Apple (Malus domestica Borkh.) is a widely cultivated fruit crop worldwide but often suffers from abiotic stresses such as salt and cold. Gibberellic acid (GA) plays a pivotal in controlling plant development, environmental adaptability, and secondary metabolism. The GA2-oxidase (GA2ox) is responsible for the deactivation of bioactive GA. In this study, seventeen GA2-oxidase genes were identified in the apple genome, and these members could be clustered into four clades based on phylogenetic relationships and conserved domain structures. MdGA2ox7 exhibited robust expression across various tissues, responded to cold and salt treatments, and was triggered in apple fruit peels via light-induced anthocyanin accumulation. Subcellular localization prediction and experiments confirmed that MdGA2ox7 was located in the cytoplasm. Overexpression of MdGA2ox7 in Arabidopsis caused a lower level of active GA and led to GA-deficient phenotypes, such as dwarfism and delayed flowering. MdGA2ox7 alleviated cold and salt stress damage in both Arabidopsis and apple in concert with melatonin (MT). Additionally, MdGA2ox7 enhanced anthocyanin biosynthesis in apple calli and activated genes involved in anthocyanin synthesis. These findings provide new insights into the functions of apple GA2ox in regulating development, stress tolerance, and secondary metabolism.
Topics: Malus; Anthocyanins; Plant Proteins; Gene Expression Regulation, Plant; Stress, Physiological; Arabidopsis; Gibberellins; Phylogeny; Plants, Genetically Modified; Melatonin
PubMed: 38763002
DOI: 10.1016/j.plaphy.2024.108707 -
Frontiers in Endocrinology 2024We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST).
INTRODUCTION
We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST).
METHODS
We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0.
RESULTS
Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH.
CONCLUSION
We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.
Topics: Humans; Male; Human Growth Hormone; Adolescent; Retrospective Studies; Child; Growth Disorders; Female; Body Height; Insulin-Like Growth Factor I; Proof of Concept Study; Dwarfism, Pituitary
PubMed: 38752175
DOI: 10.3389/fendo.2024.1398171 -
Med (New York, N.Y.) May 2024Growth and immune process dysregulation can result in both cancer and nonmalignant disease (hereditary or acquired, with and without predisposition to malignancy).... (Review)
Review
Growth and immune process dysregulation can result in both cancer and nonmalignant disease (hereditary or acquired, with and without predisposition to malignancy). Moreover, perhaps unexpectedly, many nonmalignant illnesses harbor genomic alterations indistinguishable from druggable oncogenic drivers. Therefore, targeted compounds used successfully to treat cancer may have therapeutic potential for nonmalignant conditions harboring the same target. MEK, PI3K/AKT/mTOR, fibroblast growth factor receptor (FGFR), and NRG1/ERBB pathway genes have all been implicated in both cancer and noncancerous conditions, and several cognate antagonists, as well as Bruton's tyrosine kinase inhibitors, JAK inhibitors, and CD20-directed antibodies, have established or theoretical therapeutic potential to bridge cancer and benign diseases. Intriguingly, pharmacologically tractable cancer drivers characterize a wide spectrum of disorders without malignant potential, including but not limited to Alzheimer's disease and a variety of other neurodegenerative conditions, rheumatoid arthritis, achondroplastic dwarfism, and endometriosis. Expanded repositioning of oncology agents in order to benefit benign but serious medical illnesses is warranted.
PubMed: 38749442
DOI: 10.1016/j.medj.2024.04.008 -
Advances in Therapy Jul 2024Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a... (Review)
Review
Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines. To address this, the European Achondroplasia Forum has developed a patient-held checklist to support adults with achondroplasia in managing their health. The checklist highlights key symptoms of spinal stenosis and obstructive sleep apnoea, both among the most frequent and potentially severe medical complications in adults with achondroplasia. The checklist acts as a framework to support individuals and their primary care provider in completing a routine review. General advice on issues such as blood pressure, pain, hearing, weight, adaptive aids, and psychosocial aspects are also included. The checklist provides key symptoms to be aware of, in addition to action points so that people can approach their primary care provider and be directed to the appropriate specialist, if needed. Additionally, the European Achondroplasia Forum offers some ideas on implementing the checklist during the transition from paediatric to adult care, thus ensuring the existing multidisciplinary team model in place during childhood can support in engaging individuals and empowering them to take responsibility for their own care as they move into adulthood.
Topics: Achondroplasia; Humans; Adult; Checklist; Spinal Stenosis; Europe; Transition to Adult Care; Sleep Apnea, Obstructive
PubMed: 38748332
DOI: 10.1007/s12325-024-02880-3