Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems ...likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including
, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735). Our patient also has a deleted
of the
gene family of transcription factors, which plays an important role in neural crest cell growth and differentiation. As the murine
model shows craniofacial anomalies and abnormal common carotid artery morphology, it can be hypothesised that
is involved in the pathogenesis of the craniofacial and vascular defects observed in our patient. In support of our assumption, we found in the literature another patient with a syndromic form of MA who had a deletion involving another
gene (
). In addition to describing the clinical history of our patient, we have reviewed all of the available literature concerning other patients with a 1p32p31 deletion, including cases from the Decipher database, and we have also reviewed the genetic disorders associated with MA, which is a useful guide for the diagnosis of syndromic form of MA.
Dissecting the role of TGF-b in the skin Ottaviani, Valentina; Chen, Wanjun; Joller, Nicole
The Journal of immunology (1950),
05/2023, Letnik:
210, Številka:
1_Supplement
Journal Article
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Abstract
The skin is outermost barrier in the body. Its only breaches are represented by hair follicles, which represent the only point of entrance for all the skin-sitting pathogens and commensals. ...Therefore, they can be defined as the most immunologically active sites of the skin. As such, tight regulation is needed at these sites and it is achieved not only through immune cells, but also non-hematopoietic cells like keratinocytes and fibroblasts. Example of immune cells are regulatory T cells, which are not only activated by, but also produce large amounts of TGF-b, a multifunctional cytokine, present in the body in 3 isoforms (TGF-b1,2 and 3). These isoforms have been reported to be fundamental for skin development during organogenesis and additional findings report about their role in driving cell localization in the skin as well as involvement in tissue repair. Though, litte is known about their immunological role in the skin. Upon generating a working protocol to separate skin layers and isolate cells from them, we were able to start to define the cell composition of each layer both at steady state and during inflammation. Moreover, we could detect the three TGF-b isoforms in each layer at both gene and protein level further discriminating between hematopoietic and non-hematopoietic sources. Finally, the importance of TGF-b in the skin was confirmed by experiments on TGF-b receptor I depleted mice. For the future, we are planning on defining exactly which cells secrete and respond to TGF-band confirm these findings by generating conditional KO mice. Additionally, the role of TGF-b will be assessed in world-wide skin diseases.
Intramural Research Program of NIDCR
Abstract
Myeloid cell types including conventional dendritic cells (cDCs) and macrophages are key responders to innate stimuli at epithelial barriers. They are equipped with innate receptors to sense ...danger signals and pathogens, becoming the first line of immune defense and thereby maintaining homeostasis. The expression of selected transcription factors was shown to be essential for the development of these myeloid subsets including Batf3, Notch2, Irf4, and Irf8 among others. We performed single-cell RNA expression analysis across eight different conditional KO lines and identified multiple defects across each line that compromised the development of unique subsets and also altered expression profiles on the remaining subsets. Within CD11c expressing cells, Notch2 deficiency in particular, seems to impair not only type 2 dendritic cells (cDC2) but also macrophage subsets across several tissues. Mice defective for Notch2 were shown to be susceptible to C. rodentium infection. We observed that the lack of Notch2 was accompanied by intestinal dysbiosis, which produced low-grade inflammation. The altered microbiome could be transferred to WT mice by co-housing, which suggests that the lack of either subset enabled the growth of an opportunistic microorganism that could prevail in competitive settings. Among the dysregulated innate pathways, we identified one that appears to correlate with this dysbiosis, and its deletion was sufficient to reproduce the phenotype in preliminary experiments. Collectively, we hypothesize that Notch2 deficiency alters the functional properties of the cDCs and intestinal macrophages ultimately leading to intestinal dysbiosis and a pre-pathologic inflammatory condition.
Supported by NIH intramural funding
Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as β-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under ...chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have been reported, coding mutations are scarcer. It is thus of great interest that patients have recently been described with microdeletions encompassing BCL11A. These patients display neurodevelopmental abnormalities, but whether they show increased HbF has not been reported. We have examined the hematological phenotype, HbF levels, and erythroid BCL11A expression in 3 such patients. Haploinsufficiency of BCL11A induces only partial developmental γ-globin silencing. Of greater interest is that a patient with a downstream deletion exhibits reduced BCL11A expression and increased HbF. Novel erythroid-specific regulatory elements in this region may be required for normal erythroid BCL11A expression, whereas loss of separate elements in the developing brain may explain the neurological phenotype.
•Elevation of HbF in 3 patients heterozygous for distinct 2p15-p16.1 syndrome microdeletions affecting BCL11A.•Identification of novel, putative regulatory elements downstream of BCL11A that govern its expression in erythroid cells.
Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant ...level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the
DPP6
gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The
DPP6
gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo
DPP6
exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the
DPP6
gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between
DPP6
haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.
Affective touch: A meta-analysis on sex differences Russo, Valentina; Ottaviani, Cristina; Spitoni, Grazia Fernanda
Neuroscience & biobehavioral reviews/Neuroscience and biobehavioral reviews,
January 2020, 2020-01-00, 20200101, Letnik:
108
Journal Article
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•The presence of a sex asymmetry in the tactile domain has been previously supported.•A meta-analysis is used to quantify sex differences in affective touch perception.•The size of the association ...does not vary as a function of the examined moderators.•Results are not influenced by publication bias.•Results show that women perceive affective touch as more pleasant than men.
The unmyelinated C-tactile afferents system holds a hedonic function in touch experiences, shaping social functioning in the so-called affective touch hypothesis. Despite the fact that females are recognized as more sensitive to discriminative aspects of touch and respond more positively to touch than men, sex differences in the perception of affective touch have not been extensively investigated. We aimed to fill this gap by meta-analyzing existing studies on this topic. Thirteen studies were eligible and pooled effect sizes (Hedges’ g) were compared. Random effect models were used. Results, which are not influenced by publication bias, show that there is a sex asymmetry in the pleasantness perceived during an affective tactile stimulation, with females showing higher pleasantness ratings than males. The size of the association does not vary as a function of sex distribution, age and methodological quality. Hormonal as well as evolutionary differences related to the caregiving and nurturing function of females may explain sex differences in affective touch. Results are limited by the small number of studies included in the meta-analysis.
Sanger and Next-Generation Sequencing of AAT Barzon, Valentina; Ferrarotti, Ilaria; Ottaviani, Stefania
Methods in molecular biology (Clifton, N.J.),
2024, Letnik:
2750
Journal Article
Sequencing of DNA is normally the final procedure carried out to determine the actual pathogenic variants when the techniques used for genotyping are unable to provide complete identification of both ...AAT alleles. Gene sequencing of complete SERPINA1 gene by using the Sanger method or next-generation sequencing (NGS) is crucial to enable correct diagnosis in patients with alpha1-antitrypsin deficiency caused by uncommon AAT variants.This protocol explains how to correctly sequence SERPINA1 gene both with Sanger method and NGS.
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