The goitrogenic effect of two Sudanese pearl millet cultivars in rats

info:eu-repo/semantics/publishe

Traditional fermentation increases goitrogenic activity in pearl millet

info:eu-repo/semantics/publishe

Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis

Atopic dermatitis (AD) is a common, complex inflammatory skin disorder where a defect skin barrier is central in the pathogenesis. Mutations in the filaggrin gene cause ichthyosis vulgaris (IV). IV is one of several keratinization disorders named ichthyoses where mutations in skin barrier genes are a common underlying genetic factor. Furthermore, filaggrin mutations are a major risk factor for moderate to severe AD. The aim of the work reported in this thesis is to improve the understanding of the genetic mechanisms of skin barrier defects associated with AD, and to identify whether AD and other common disorders of keratinisation may share genetic susceptibility factors related to skin barrier dysfunction. Paper I presents data suggesting that filaggrin mutations may be rare in Ethiopian AD and IV patients, implying other mechanisms should be more important in the pathogenesis of IV and AD in this ethnic group. Paper II presents a novel mutation in the steroid sulfatase gene in a patient with clinical signs of common ichthyosis type. In paper III association between filaggrin mutations and childhood onset of psoriasis was tested. No association to any prevalent filaggrin mutations was found, and no novel mutations. This indicates that filaggrin loss-of- function variants do not have a strong effect on the onset of psoriasis in childhood. In paper IV it is demonstrated that functional parameters and gene expression in molecular pathways in vivo is altered in patients suffering from AD and IV and depend on filaggrin genotype. Patients with filaggrin mutations displayed a severe phenotype with impaired barrier function measured as increased trans-epidermal water loss, and significantly altered pH levels. Furthermore, the numbers of genes with altered expression were significantly higher in patients with low or absent filaggrin expression. These pathways include many genes involved in inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion. Paper V represents a candidate gene study where expression analysis links the epidermal transglutaminases 1 and 3 to the manifestation of AD and genetic analysis suggests that genetic variation at the transglutaminase 1 locus could be involved in the development of the disease. The results of the work reported in this thesis provides additional descriptive information and further elucidates the pathogenesis underlying AD and other disorders of keratinization, in particular in relation to filaggrin deficiency. Better understanding of the genetic factors and molecular and functional consequences should hopefully enable future individually designed barrier restoring therapy

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Item does not contain fulltextPURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Purpose: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22–p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene–disease validity for the purpose of diagnostic reporting

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Purpose: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22–p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene–disease validity for the purpose of diagnostic reporting