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GLI family zinc finger proteins are transcriptional effectors of the sonic hedgehog signaling pathway. GLI regulates gene expression and repression at various phases of embryonic morphogenesis. In humans, 4 GLI genes are known, and GLI2 (2q14.2) and GLI3 (7p14.1) mutations cause different syndromes. Here, we present 2 distinctive cases with a chrom...
Citations
... Some patients manifest polydactyly, mostly postaxial without syndactyly, and variable degrees of intellectual and socio-behavioural disabilities. Genotype-phenotype correlations do not appear to fit the typically expected pattern: missense mutations are not always milder than truncating mutations, and point mutations are not always milder than chromosomal microdeletions [66]. Although patients with large chromosomal deletions tend to have complicating visceral malformations, such as congenital heart defects, heterotaxy, and urogenital defects, the phenotypic spectra of point mutations and chromosomal deletions generally overlap and can be difficult to distinguish. ...
... HPE9 is characterized by a wide phenotypic spectrum of brain developmental defects, with or without overt forebrain cleavage abnormalities (holoprosencephaly). To date, many case reports and reviews of human GLI2 defects associated with HPE9 have been made [69][70][71], and the actual phenotypic spectra of these syndromes have been clarified [66]. ...
Human hereditary malformation syndromes are caused by mutations in the genes of the signal transduction molecules involved in fetal development. Among them, the Sonic hedgehog (SHH) signaling pathway is the most important, and many syndromes result from its disruption. In this review, we summarize the molecular mechanisms and role in embryonic morphogenesis of the SHH pathway, then classify the phenotype of each malformation syndrome associated with mutations of major molecules in the pathway. The output of the SHH pathway is shown as GLI activity, which is generated by SHH in a concentration-dependent manner, i.e., the sum of activating form of GLI (GLIA) and repressive form of GLI (GLIR). Which gene is mutated and whether the mutation is loss-of-function or gain-of-function determine in which concentration range of SHH the imbalance occurs. In human malformation syndromes, too much or too little GLI activity produces symmetric phenotypes affecting brain size, craniofacial (midface) dysmorphism, and orientation of polydactyly with respect to the axis of the limb. The symptoms of each syndrome can be explained by the GLIA/R balance model.
... 1 Thus, the GLI2 gene has been implicated to be involved in forebrain, pituitary, and limb development. 2,3,8,9,11 In this series, we present a family, two daughters and a mother, with an identical GLI2 gene mutation. Sisters 1 and 2 present with the classic dyad of findings in a patient with Culler Jones syndrome of growth hormone (GH) deficiency and postaxial polydactyly, and their mother also demonstrated postaxial polydactyly at birth but otherwise has an unremarkable phenotype. ...
This case series and review of the literature support that patients with pathogenic variants of the GLI2 gene demonstrate an autosomal dominant inheritance pattern, variable expressivity, and incomplete penetrance.
... YAP is a downstream gene of the Hippo pathway that suppresses cancer development. Hippo signaling pathway deactivation can lead to YAP protein transfer from cytoplasm to nucleus and storage in the nucleus, after which YAP stimulates CTGF and Gli2, which were target genes of YAP, and increases cancer cell 7040 proliferation [21][22][23][24]. By analyzing the differences in expressions of YAP, CTGF, and Gli2 proteins in different stages of breast cancer, we found that YAP, CTGF, and Gli2 proteins were significantly higher in breast cancer patients compared with those in patients with benign tumors. ...
Background
The aim of this study was to assess the correlation between Doppler ultrasound blood flow parameters and angiogenesis and proliferation activity in breast cancer.
Material/Methods
We enrolled breast cancer patients (n=55) and benign tumor patients (n=40) from Tengzhou Central People’s Hospital from Mar 2014 to Dec 2016. Doppler ultrasound examination was conducted to determine blood flow parameters, and immunohistochemistry (IHC) experiments were performed to determine the protein expression of angiogenesis genes, cell proliferation genes, and tumor-suppressor genes.
Results
Compared with benign tumors, the maximum velocity (Vmax) and resistance index (RI) were significantly different in I–II stage and III–IV stage breast cancer (P<0.01 and P<0.001, respectively). IHC assay showed that VEDGF165, NRP-1, SphK1, CD31, YAP, CTGF, and Gli2 proteins expressions were significantly higher in breast cancer patients (P<0.01 and P<0.001, respectively). PTEN and MFN2 protein expressions of breast cancer patients were significantly lower (P<0.01 or P<0.001, respectively) compared with those of benign tumor patients. VEDGF165, NRP-1, SphK1, CD31, YAP, CTGF, and Gli2 proteins expressions were positively correlated with Vmax and negatively correlated with RI in breast cancer. PTEN and MFN2 protein expressions were negative correlated with Vmax and positively correlated with RI in breast cancer patients.
Conclusions
Decreased RI and increased Vmax are correlated with angiogenesis, proliferation, and tumor suppression in breast cancer.
... HPE9 also shows incomplete penetrance and variable expressivity. Actually, these two conditions represent a continuous phenotypic spectrum, with the milder forms referred to as CJS and the more severe cases referred to as HPE9 [10]. As the inheritance pattern is usually autosomal dominant [2] with incomplete penetrance, the mutation is frequently inherited from an asymptomatic parent. ...
... She had learning difficulties in school, social communication problems and was diagnosed with selective mutism. She had short stature and delayed puberty [92]. ...
... It is caused by the loss of function of GLI3 gene and is inherited in an autosomal dominant pattern [93]. Individuals with large deletions encompassing GLI3 show more severe phenotype [57,92]. Mutations in the 5 region close to the or within the zinc finger domain cause the majority of GCPS [94], other mutations have been detected, such as missense, splicing or truncating mutations elsewhere in the gene. ...
GLI transcription factors have important roles in intracellular signaling cascade, acting as the main mediators of the HH-GLI signaling pathway. This is one of the major developmental pathways, regulated both canonically and non-canonically. Deregulation of the pathway during development leads to a number of developmental malformations, depending on the deregulated pathway component. The HH-GLI pathway is mostly inactive in the adult organism but retains its function in stem cells. Aberrant activation in adult cells leads to carcinogenesis through overactivation of several tightly regulated cellular processes such as proliferation, angiogenesis, EMT. Targeting GLI transcription factors has recently become a major focus of potential therapeutic protocols.
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Graphical Abstract
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BACKGROUND
Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage.
OBJECTIVE
To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy.
METHODS
Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions.
EXPECTED OUTCOMES
With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine.
DISCUSSION
The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.
Background: Neurodevelopmental disorders have a prevalence of approximately 3% in the population, the genetic factor is involved in this condition. Microdeletions that comprise the 2q14.1q14.3 region are rare events. The aim of the study: To describe a girl with an interstitial deletion of the 2q14 region with a severely affected phenotype and to compare her with reports from the international literature. Materials and methods: Cell culture and the obtaining of chromosomes were carried out according to the standardized techniques in our laboratory. Results: Girl evaluated for dismorphias and brain malformation (corpus callosum agenesis). The chromoso-mal study with a resolution of 565 bands showed an interstitial deletion in the long arm of chromosome 2. Karyotype: 46, XX, del (2) (q14.1q14.2). Conclusion: The correct clinical analysis of the patient and the high-resolution cytogenetic technique has been successful for detection of the microdeletion in this case helping in genetic counseling and in elucidating the genetic origin of the patient's neurodevelopmental disorder.
Background
Agenesis of the corpus callosum (ACC) is a relatively common brain malformation in children with developmental disabilities, caused by mutations in many genes. These genetic causes are characterized by their extreme heterogeneity with more than 300 causative genes identified to date.
Case report
We describe two new cases from a three-generation family with ACC and a de novo mutation of the sonic hedgehog (SHH) gene. The affected family members had mild intellectual disability, broad forehead, and widely spaced eyes. A next-generation sequencing (NGS) approach revealed a stop-gain mutation (NM_000193.2:c.1300_1301insA p.Trp434Ter) of the SHH gene; it is the first family to report ACC associated with a single SHH gene mutation.
Conclusion
ACC with mild intellectual disability and facial dysmorphism may be caused by a mutation in SHH, but further research investigating the genotype-phenotype correlation of SHH mutations is required.
Background:
Polydactyly, characterized by supernumerary digits in the upper or lower extremities, is the most common congenital digital abnormalities. It derives from the defective patterning of anteroposterior axis of the developing limb, with various etiology and clinical heterogeneity. The patients with post-axial polydactyly type A (PAPA) have the typical symptom of a well-formed supernumerary digit outside the fifth digit.
Objective:
The aim of present study was to identify the causative mutations of two unrelated Han Chinese patients with non-syndromic PAPA.
Methods:
Two unrelated Han Chinese patients and 100 ethnicity-matched, unrelated normal controls were recruited for this study. BGISEQ-500 exome sequencing was performed in the two patients, followed by validation in the patients and 100 controls by using Sanger sequencing.
Results:
Two mutations in the GLI family zinc finger 3 gene (GLI3), including a frameshift mutation c.3437_3453delTCGAGCAGCCCTGCCCC (p.L1146RfsX95) and a nonsense mutation c.3997C>T (p.Q1333X), were identified in two patients but were absent in the 100 healthy controls.
Conclusion:
The two GLI3 mutations, p.L1146RfsX95 and p.Q1333X, may account for non-syndromic PAPA in the two patients, respectively. The findings of this study may expand the mutational spectrum of GLI3-PAPA and provide novel insights into the genetic basis of polydactyly.
