ITPR1 Mutation Contributes to Hemifacial Microsomia Spectrum

Hemifacial microsomia (HM) is a craniofacial congenital defect involving the first and second branchial arch, mainly characterized by ocular, ear, maxilla-zygoma complex, mandible, and facial nerve malformation. HM follows autosomal dominant inheritance. Whole-exome sequencing of a family revealed a missense mutation in a highly conserved domain of ITPR1. ITPR1 is a calcium ion channel. By studying ITPR1’s expression pattern, we found that ITPR1 participated in craniofacial development, especially the organs that corresponded to the phenotype of HM. In zebrafish, itpr1b, which is homologous to human ITPR1, is closely related to craniofacial bone formation. The knocking down of itpr1b in zebrafish could lead to a remarkable decrease in craniofacial skeleton formation. qRT-PCR suggested that knockdown of itpr1b could increase the expression of plcb4 while decreasing the mRNA level of Dlx5/6. Our findings highlighted ITPR1’s role in craniofacial formation for the first time and suggested that ITPR1 mutation contributes to human HM.

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AN INSIGHT INTO - HEMIFACIAL MICROSOMIA

International Journal of Advanced Research ◽

10.21474/ijar01/13475 ◽

2021 ◽

Vol 9 (09) ◽

pp. 734-739

Author(s):

Nivedita Sahoo ◽

Rajat Mohanty ◽

Arpita Singh ◽

Bhagabati Prasad Dash ◽

Kanika Singh Dhull

Keyword(s):

Central Nervous System ◽

Birth Defect ◽

Autosomal Dominant ◽

Branchial Arch ◽

Craniofacial Anomalies ◽

Hemifacial Microsomia ◽

Dominant Inheritance ◽

Familial Cases ◽

Central Nervous System Defects ◽

Insight Into

Hemifacial microsomia is a common birth defect involving first and second branchial arch derivatives. The phenotype is highly variable. In addition to craniofacial anomalies, there may be cardiac, vertebral, and central nervous system defects. Most cases are sporadic, but there are rare familial cases that exhibit autosomal dominant inheritance.

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Non-Syndromal Hemifacial Microsomia in Two Iraqi Children.

10.46940/gjsst.01.1001 ◽

2019 ◽

pp. 1-3

Keyword(s):

Facial Asymmetry ◽

Rare Condition ◽

Branchial Arch ◽

Multidisciplinary Teams ◽

Hemifacial Microsomia ◽

The World ◽

The Face ◽

Associated Malformations ◽

First Time ◽

Static Nature

Abstract Hemifacial microsomia is a rare congenital, heterogeneous malformation disorder affecting predominantly unilateral face and involving head malformations mainly in the region of the first and second branchial arch and varying associated malformations. The disorder is associated with unusual strange distortion of the face with facial asymmetry and may cause psychological problems in the affected child and even the parents. Hemifacial microsomia is best managed by a multidisciplinary team including the otolaryngologist, audiologist, plastic surgeon and temporal bone radiologist. However, physicians working in many geographic areas of the world lacking active effective multidisciplinary teams and major craniofacial centers, will face a serious challenge and a tough time in making the appropriate referrals which ensure satisfactory management. The complexity of the defects in this condition, the potentially non-static nature of the condition and the lack of extensive management experiences with such rare condition make management challenging even when the appropriate timely referrals can be ensured. The aim of this paper is to report the occurrence of non-syndromal hemifacial microsomia in two unrelated Iraqi children for the first time.

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Antiticiombin III Deficiency In A Large Family with 41 Affected Members

10.1055/s-0038-1653102 ◽

1981 ◽

Author(s):

J Stibbe ◽

S Adhin ◽

G L Ong ◽

R S Panday ◽

S H Peters ◽

...

Keyword(s):

Autosomal Dominant ◽

Large Family ◽

Clinical Information ◽

Impedance Plethysmography ◽

Age Group ◽

Oral Contraceptive Pills ◽

Contraceptive Pills ◽

At Iii ◽

L 51 ◽

First Time

Hereditary Antithrombin III (AT III) deficiency was found in a large Hindustani family, living partly in the Netherlands, partly in Suriname. Of 201 members investigated 35 were found to affected: AT III activity (chromogenic substrate) and AT III antigen (immuno-electrophoresis according to Laurell) were about 45 %. Analysis of this fanily clearly demonstrated the autosomal dominant inheritance of the condition. Six non-investigated members (1 living, 5 non-living) were diagnosed as being affected on the basis of affected offspring.Seventeen affected members had no signs of thrombo-embolic(TE) processes (age group 0-10 years old, n=2; 11-20, n=5; 21-30, n=4; 31-40, n=4; 41-50, n=2). Thirteen showed clinical or proven signs of TE processes (first time in age group 0-10 years old, n=0; 11-20, n=l; 21-30, n=G; 31-40, n=4; 41-50,n=l; 51-60, n=0; 61-70, n=l). No clinical information is yet available on the remaining affected members. Deep venous thrombosis (DVT) occurred in 9 patients (age group 21-30, n=5; 31-40, n=3; 61-70, n=l). Triggering factors were none 4, surgery 1, oral contraceptives and preg- nancy4. Pulmonary embolism occurred in 6 patients (2 clinical, 4 proven) and was fatal in 4; ages were 19, 21, 26, 37, 48 and 68 years old. Pregnancy was uncomplicated in 3 women (total of 4 pregnancies), one of these women was treated prophylactically with anticoagulants during pregnancy (1 pregnancy). Two women (9 pregnancies) had a thrombotic episode (1st and 3rd pregnancy respectively) and 1 woman died suddenly 7 days after her 7th childbirth. DVT occurred in 2 of 4 women who used oral contraceptive pills.In some symptomless patients (age 22, 26, 32, 33, 40 years old) impedance plethysmography (n=5), 125I-fibrinogen leg scanning (n=3), 125I-fibrinogen T½(n=3) and 51C-platelet survival (n=l) were normal

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The Assessment of IL-21 and IL-22 at the mRNA Level in Tumor Tissue and Protein Concentration in Serum and Peritoneal Fluid in Patients with Ovarian Cancer

Journal of Clinical Medicine ◽

10.3390/jcm10143058 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3058

Author(s):

Aleksandra Mielczarek-Palacz ◽

Celina Kruszniewska-Rajs ◽

Marta Smycz-Kubańska ◽

Jarosław Strzelczyk ◽

Wojciech Szanecki ◽

...

Keyword(s):

Ovarian Cancer ◽

Peritoneal Fluid ◽

Tumor Tissue ◽

Mrna Level ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Expression Of Genes ◽

Genes Encoding ◽

First Time ◽

Ovarian Serous Cancer

The aim of the analysis was for the first time to assess the expression of genes encoding IL-21 and IL-22 at the mRNA level in ovarian tumor specimens and the concentration of these parameters in serum and peritoneal fluid in patients with ovarian serous cancer. The levels of IL-21 and IL-22 transcripts were evaluated with the use of the real-time RT-qPCR. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of proteins. Quantitative analysis of IL-21 gene mRNA in the tumor tissue showed the highest activity in the G1 degree of histopathological differentiation and was higher in G1 compared to the control group. The concentration of IL-21 and IL-22 in the serum and in the peritoneal fluid of women with ovarian cancer varied depending on the degree of histopathological differentiation of the cancer and showed statistical variability compared to controls. The conducted studies have shown that the local and systemic changes in the immune system involving IL-21 and IL-22 indicate the participation of these parameters in the pathogenesis of ovarian cancer, and modulation in the IL-21/IL-22 system may prove useful in the development of new diagnostic and therapeutic strategies used in patients, which require further research.

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A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Translational Stroke Research ◽

10.1007/s12975-021-00926-0 ◽

2021 ◽

Author(s):

Qing Li ◽

Chengfeng Wang ◽

Wei Li ◽

Zaiqiang Zhang ◽

Shanshan Wang ◽

...

Keyword(s):

Basement Membrane ◽

Skin Biopsy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Heterozygous Mutation ◽

Collagen Type Iv ◽

Lacunar Infarcts ◽

Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

Child Neurology Open ◽

10.1177/2329048x211006511 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110065

Author(s):

Nesrin Şenbil ◽

Zeynep Arslan ◽

Derya Beyza Sayın Kocakap ◽

Yasemin Bilgili

Keyword(s):

Corpus Callosum ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Gene Mutations ◽

Hirschsprung Disease ◽

Agenesis Of Corpus Callosum ◽

Whole Exome ◽

Congenital Cardiac Anomalies ◽

History Of ◽

Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

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Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

Cancers ◽

10.3390/cancers13102403 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2403

Author(s):

Chenghui Zhou ◽

Zhefang Wang ◽

Jiahui Li ◽

Xiaolin Wu ◽

Ningbo Fan ◽

...

Keyword(s):

Esophageal Adenocarcinoma ◽

Mrna Level ◽

Chemotherapy Resistance ◽

Poor Overall Survival ◽

Akt Phosphorylation ◽

Tumor Tissues ◽

Novel Strategy ◽

Induced Apoptosis ◽

First Time ◽

Eac Cells

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

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A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia

BioMed Research International ◽

10.1155/2021/6678531 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Bing-Bing Guo ◽

Jie-Yuan Jin ◽

Zhuang-Zhuang Yuan ◽

Lei Zeng ◽

Rong Xiang

Keyword(s):

Extracellular Matrix ◽

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Autosomal Dominant ◽

Novel Mutation ◽

Chinese Family ◽

The Novel ◽

Structure Model ◽

Whole Exome ◽

Nucleotide Mutation

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

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αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum

PLoS ONE ◽

10.1371/journal.pone.0235136 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0235136

Author(s):

Sara Morais ◽

Jorge Oliveira ◽

Catarina Lau ◽

Mónica Pereira ◽

Marta Gonçalves ◽

...

Keyword(s):

Binding Sites ◽

Autosomal Dominant ◽

Transmembrane Domain ◽

Laboratory Data ◽

Atp Release ◽

Cytoplasmic Domains ◽

Pathogenic Variants ◽

Distinct Disease ◽

And Function ◽

First Time

Background Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

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Prenatal Diagnosis of Holt–Oram Syndrome With a Novel Mutation of TBX5 Gene: A Case Report

Frontiers in Pediatrics ◽

10.3389/fped.2021.737633 ◽

2021 ◽

Vol 9 ◽

Author(s):

Guan-nan He ◽

Xue-yan Wang ◽

Min Kang ◽

Xi-min Chen ◽

Na Xi ◽

...

Keyword(s):

Septal Defect ◽

Autosomal Dominant ◽

Novel Mutation ◽

Splice Donor ◽

Autosomal Dominant Disorder ◽

Cubitus Valgus ◽

Case Presentation ◽

Whole Exome ◽

The Right ◽

Tbx5 Gene

Background: Holt–Oram syndrome (HOS) is an autosomal dominant disorder caused by mutations of TBX5 gene.Case presentation: We report a fetus with HOS diagnosed sonographically at 23 weeks of gestation. The fetal parents are non-consanguineous. The fetus exhibited short radius and ulna, inability to supinate the hands, absence of the right thumb, and heart ventricular septal defect (VSD), while the fetal father exhibited VSD and short radius and ulna only. Fetal brother had cubitus valgus and thumb adduction, except for VSD, short radius and ulna. The pregnancy was terminated. Whole-exome sequencing (WES) revealed a novel mutation in the TBX5 (c.510+1G>A) in the fetus inherited from the father. The variant (c.510+1G>A) occurs at splice donor and may alter TBX5 gene function by impact on splicing. It was not previously reported in China.Conclusion: Our case reported a novel mutation in TBX5, which expanded the known genetic variants associated with HOS.

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