scholarly journals Cecr2 mutant mice as a model for human cat eye syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Renée Dicipulo ◽  
Kacie A. Norton ◽  
Nicholas A. Fairbridge ◽  
Yana Kibalnyk ◽  
Sabrina C. Fox ◽  
...  
Keyword(s):  
Chromosome Region ◽  
Heart Defects ◽  
Genetic Disorder ◽  
Mouse Strains ◽  
Loss Of Function ◽  
Cat Eye Syndrome ◽  
Inverted Duplication ◽  
Wide Range ◽  
Human Genetic Disorder ◽  
Shed Light

AbstractCat eye syndrome (CES), a human genetic disorder caused by the inverted duplication of a region on chromosome 22, has been known since the late 1890s. Despite the significant impact this disorder has on affected individuals, models for CES have not been produced due to the difficulty of effectively duplicating the corresponding chromosome region in an animal model. However, the study of phenotypes associated with individual genes in this region such as CECR2 may shed light on the etiology of CES. In this study we have shown that deleterious loss of function mutations in mouse Cecr2 effectively demonstrate many of the abnormal features present in human patients with CES, including coloboma and specific skeletal, kidney and heart defects. Beyond phenotypic analyses we have demonstrated the importance of utilizing multiple genetic backgrounds to study disease models, as we see major differences in penetrance of Cecr2-related abnormal phenotype between mouse strains, reminiscent of the variability in the human syndrome. These findings suggest that Cecr2 is involved in the abnormal features of CES and that Cecr2 mice can be used as a model system to study the wide range of phenotypes present in CES.

scholarly journals Zebrafish mbnl mutants model physical and molecular phenotypes of myotonic dystrophy

2019 ◽  
Author(s):  
Melissa N. Hinman ◽  
Jared I. Richardson ◽  
Rose A. Sockol ◽  
Eliza D Aronson ◽  
Sarah J. Stednitz ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Myotonic Dystrophy ◽  
Protein Function ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
High Fecundity ◽  
Molecular Phenotypes ◽  
Human Genetic Disorder

AbstractThe muscleblind RNA binding proteins (MBNL1, MBNL2, and MBNL3) are highly conserved across vertebrates and are important regulators of RNA alternative splicing. Loss of MBNL protein function through sequestration by CUG or CCUG RNA repeats is largely responsible for the phenotypes of the human genetic disorder myotonic dystrophy (DM). We generated the first stable zebrafish (Danio rerio) models of DM-associated MBNL loss of function through mutation of the three zebrafish mbnl genes. In contrast to mouse models, zebrafish double and triple homozygous mbnl mutants were viable to adulthood. Zebrafish mbnl mutants displayed disease-relevant physical phenotypes including decreased body size and impaired movement. They also exhibited widespread alternative splicing changes, including the misregulation of many DM-relevant exons. Physical and molecular phenotypes were more severe in compound mbnl mutants than in single mbnl mutants, suggesting partially redundant functions of Mbnl proteins. The high fecundity and larval optical transparency of this complete series of zebrafish mbnl mutants will make them useful for studying DM-related phenotypes and how individual Mbnl proteins contribute to them, and for testing potential therapeutics.

scholarly journals Zebrafish mbnl mutants model physical and molecular phenotypes of myotonic dystrophy

2021 ◽  
Author(s):  
Melissa N. Hinman ◽  
Jared I. Richardson ◽  
Rose A. Sockol ◽  
Eliza D Aronson ◽  
Sarah J. Stednitz ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Myotonic Dystrophy ◽  
Protein Function ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
High Fecundity ◽  
Molecular Phenotypes ◽  
Human Genetic Disorder

The muscleblind RNA binding proteins (MBNL1, MBNL2, and MBNL3) are highly conserved across vertebrates and are important regulators of RNA alternative splicing. Loss of MBNL protein function through sequestration by CUG or CCUG RNA repeats is largely responsible for the phenotypes of the human genetic disorder myotonic dystrophy (DM). We generated the first stable zebrafish (Danio rerio) models of DM-associated MBNL loss of function through mutation of the three zebrafish mbnl genes. In contrast to mouse models, zebrafish double and triple homozygous mbnl mutants were viable to adulthood. Zebrafish mbnl mutants displayed disease-relevant physical phenotypes including decreased body size and impaired movement. They also exhibited widespread alternative splicing changes, including the misregulation of many DM-relevant exons. Physical and molecular phenotypes were more severe in compound mbnl mutants than in single mbnl mutants, suggesting partially redundant functions of Mbnl proteins. The high fecundity and larval optical transparency of this complete series of zebrafish mbnl mutants will make them useful for studying DM-related phenotypes and how individual Mbnl proteins contribute to them, and for testing potential therapeutics.

scholarly journals SUN-074 Loss-Of-Function Mutations in GATA4 in Patients with 46,XY Disorders of Sex Development Without Cardiac Defects

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yena Lee ◽  
Arum Oh ◽  
Han-Wook Yoo ◽  
Jin-Ho Choi
Keyword(s):  
Heart Defects ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Luciferase Reporter ◽  
Molecular Characteristics ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Sex Development ◽  
Wide Range

Abstract Background: Disorders of sex development (DSD) encompass a wide range of conditions associated with numerous causative genes. In about 50-60% of 46,XY DSD individuals, the underlying molecular cause remains uncertain. GATA4 haploinsufficiency has been described in patients with congenital heart defects (CHD), while only a few studies reported mutations related to 46,XY DSD phenotype. This study investigated clinical phenotypes and molecular characteristics of two 46,XY DSD patients with GATA4 mutations. Methods: Mutation analysis was performed in patients with 46,XY DSD by whole exome sequencing (WES) using Illumina NextSeq platform. Clinical and endocrine characteristics were reviewed retrospectively. GATA4 variants identified by WES were verified by Sanger sequencing. Functional activity of GATA4 variants was tested by luciferase reporter assay on the SRY and AMH promoter using two different cell systems including HEK293 and NCI-H295R. Results: Subject 1 presented with micropenis and hypospadias at the age of 5 months. Karyotype was 46,XY. Mullerian duct remnants were not found in pelvic ultrasound. The patient underwent urethroplasty at the age of 10 months and was reared as a male. Subject 2 with complete female external genitalia was referred to our hospital because of 46,XY karyotype on G-scanning. The patient underwent laparoscopic orchiectomy at the age of 1.8 years and was assigned as a female. Both patients were responsive to hCG stimulation tests and did not have CHD. Subject 1 harbored a novel heterozygous variant of c.643A>G (p.R215G)] in GATA4, whereas a previously reported variant of c.1220C>A (p.P407Q) was identified in Subject 2. In vitro luciferase reporter assays using SRY and AMH promoter revealed decreased transcriptional activity of both p.P407Q and p.R215G. Conclusions: This study expanded phenotypic spectrum of mutations in GATA4 in patients with 46,XY DSD without CHD. GATA4 mutations in patients with 46,XY DSD may not be associated with CHD. Possible explanations for phenotypical variability comprise incomplete penetrance, variable expressivity, and oligogenic mechanisms.

Sentence-Based Experience Logging in New Hearing Aid Users

2020 ◽  
Vol 29 (3S) ◽  
pp. 631-637
Author(s):  
Katja Lund ◽  
Rodrigo Ordoñez ◽  
Jens Bo Nielsen ◽  
Dorte Hammershøi
Keyword(s):  
Hearing Aid ◽  
Patient Experiences ◽  
Online Tool ◽  
Rehabilitation Process ◽  
Hearing Rehabilitation ◽  
Clinical Observations ◽  
Hearing Aid Use ◽  
Wide Range ◽  
Insight Into ◽  
Shed Light

Purpose The aim of this study was to develop a tool to gain insight into the daily experiences of new hearing aid users and to shed light on aspects of aided performance that may not be unveiled through standard questionnaires. Method The tool is developed based on clinical observations, patient experiences, expert involvement, and existing validated hearing rehabilitation questionnaires. Results An online tool for collecting data related to hearing aid use was developed. The tool is based on 453 prefabricated sentences representing experiences within 13 categories related to hearing aid use. Conclusions The tool has the potential to reflect a wide range of individual experiences with hearing aid use, including auditory and nonauditory aspects. These experiences may hold important knowledge for both the patient and the professional in the hearing rehabilitation process.

Role of Cardiac MRI in Detecting Familial Hypertrophic Cardiomyopathy: Review

2016 ◽  
Vol 1 (1) ◽  
pp. 4
Author(s):  
Marymol Koshy ◽  
Bushra Johari ◽  
Mohd Farhan Hamdan ◽  
Mohammad Hanafiah
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Magnetic Resonance ◽  
Genetic Disorder ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Non Invasive ◽  
Wide Range ◽  
Proper Diagnosis ◽  
Magnetic Resonance Imaging Mri ◽  
Potential Use

Hypertrophic cardiomyopathy (HCM) is a global disease affecting people of various ethnic origins and both genders. HCM is a genetic disorder with a wide range of symptoms, including the catastrophic presentation of sudden cardiac death. Proper diagnosis and treatment of this disorder can relieve symptoms and prolong life. Non-invasive imaging is essential in diagnosing HCM. We present a review to deliberate the potential use of cardiac magnetic resonance (CMR) imaging in HCM assessment and also identify the risk factors entailed with risk stratification of HCM based on Magnetic Resonance Imaging (MRI).

Clinical and molecular cytogenetic characterization of two cases of inverted duplication deletion 8p

2020 ◽  
pp. 41-42
Author(s):  
Д.А. Юрченко ◽  
М.Е. Миньженкова ◽  
Е.Л. Дадали ◽  
Н.В. Шилова
Keyword(s):  
Mental Retardation ◽  
Congenital Heart ◽  
Heart Defects ◽  
Clinical Manifestations ◽  
Formation Mechanisms ◽  
Agenesis Of Corpus Callosum ◽  
Molecular Cytogenetic ◽  
Inverted Duplication ◽  
Cytogenetic Characterization

Синдром инвертированной дупликации короткого плеча хромосомы 8 со смежной терминальной делециенй (inv dup del(8p), ORPHA 96092) - редкая хромосомная аномалия (ХА) с частотой 1/10000-1/30000 живорожденных. В статье представлены клинические и молекулярно-цитогенетические характеристики двух неродственных пациентов с синдромом inv dup del(8p) и уточнены механизмы формирования хромосомного дисбаланса. Inverted duplication deletion 8p syndrome (inv dup del(8p), ORPHA 96092) is a rare chromosomal abnormality with a frequency of 1:10,000 - 30,000 newborns. Clinical manifestations of this syndrome include mental retardation, facial anomalies, hypoplasia/agenesis of corpus callosum, scoliosis and/or kyphosis, hypotonia, congenital heart defects. The article presents the clinical and molecular cytogenetic characteristics of two patients with inv dup del (8p) syndrome and clarifies the formation mechanisms.

scholarly journals Mini-Review Regarding the Applicability of Genome Editing Techniques Developed for Studying Infertility

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 246
Author(s):  
Bogdan Doroftei ◽  
Ovidiu-Dumitru Ilie ◽  
Maria Puiu ◽  
Alin Ciobica ◽  
Ciprian Ilea
Keyword(s):  
Motor Activity ◽  
Experimental Model ◽  
Zinc Finger ◽  
Biomedical Research ◽  
Zinc Finger Nucleases ◽  
Loss Of Function ◽  
Transcription Activator ◽  
Phenotypic Changes ◽  
Wide Range ◽  
Short Palindromic Repeat

Infertility is a highly debated topic today. It has been long hypothesized that infertility has an idiopathic cause, but recent studies demonstrated the existence of a genetic substrate. Fortunately, the methods of editing the human genome proven to be revolutionary. Following research conducted, we identified a total of 21 relevant studies; 14 were performed on mice, 5 on zebrafish and 2 on rats. We concluded that over forty-four genes in total are dispensable for fertility in both sexes without affecting host homeostasis. However, there are genes whose loss-of-function induces moderate to severe phenotypic changes in both sexes. There were situations in which the authors reported infertility, exhibited by the experimental model, or other pathologies such as cryptorchidism, cataracts, or reduced motor activity. Overall, zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 are techniques that offer a wide range of possibilities for studying infertility, even to create mutant variants. It can be concluded that ZFNs, TALENs, and CRISPR/Cas9 are crucial tools in biomedical research.

scholarly journals Inborn errors of immunity—recent advances in research on the pathogenesis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Motoi Yamashita ◽  
Kento Inoue ◽  
Tsubasa Okano ◽  
Tomohiro Morio
Keyword(s):  
Immune System ◽  
Hematopoietic Cell Transplantation ◽  
Epigenetic Modification ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Whole Genome Analysis ◽  
Curative Therapy ◽  
Inborn Errors Of Immunity ◽  
Recent Advances

AbstractPrimary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.

scholarly journals Beyond cultural and geographical proximity: delving into the factors that influence the dynamics of academic relationships between students in higher education

2021 ◽  
Author(s):  
José-Vicente Tomás-Miquel ◽  
Jordi Capó-Vicedo
Keyword(s):  
University Students ◽  
Academic Research ◽  
Past Research ◽  
Academic Networks ◽  
Level Data ◽  
Wide Range ◽  
Specific Stage ◽  
The University ◽  
Proximity Dimensions ◽  
Shed Light

AbstractScholars have widely recognised the importance of academic relationships between students at the university. While much of the past research has focused on studying their influence on different aspects such as the students’ academic performance or their emotional stability, less is known about their dynamics and the factors that influence the formation and dissolution of linkages between university students in academic networks. In this paper, we try to shed light on this issue by exploring through stochastic actor-oriented models and student-level data the influence that a set of proximity factors may have on formation of these relationships over the entire period in which students are enrolled at the university. Our findings confirm that the establishment of academic relationships is derived, in part, from a wide range of proximity dimensions of a social, personal, geographical, cultural and academic nature. Furthermore, and unlike previous studies, this research also empirically confirms that the specific stage in which the student is at the university determines the influence of these proximity factors on the dynamics of academic relationships. In this regard, beyond cultural and geographic proximities that only influence the first years at the university, students shape their relationships as they progress in their studies from similarities in more strategic aspects such as academic and personal closeness. These results may have significant implications for both academic research and university policies.

scholarly journals Messianism, rationalism and inter-Asian connections: The Majalis-i Jahangiri (1608–11) and the socio-intellectual history of the Mughal ‘ulama

2017 ◽  
Vol 54 (3) ◽  
pp. 317-338 ◽  
Author(s):  
Corinne Lefèvre
Keyword(s):  
Central Asia ◽  
Intellectual History ◽  
State Building ◽  
Specific Role ◽  
Wide Range ◽  
History Of ◽  
Muslim Intellectuals ◽  
Shed Light

Relying on the Majalis-i Jahangiri (1608–11) by ʿAbd al-Sattar b. Qasim Lahauri, this essay explores some of the discussions the Mughal Emperor Jahangir (r. 1605–27) conducted with a wide range of scholars, from Brahmans and ʿulama to Jesuit padres and Jewish savants. By far the most numerous, the debates bearing on Islam and involving Muslim intellectuals are especially significant on several accounts. First, because they illuminate how, following in the steps of his father Akbar (r. 1556–605), Jahangir was able to conciliate his messianic claims with a strong engagement with reason and to turn this combination into a formidable instrument for confession and state building. These conversations also provide promising avenues to think afresh the socio-intellectual history of the Mughal ʿulama inasmuch as they capture the challenges and adjustments attendant on imperial patronage, depict the jockeying for influence and positions among intellectuals (particularly between Indo-Muslim and Iranian lettrés), and shed light on relatively little known figures or on unexplored facets of more prominent individuals. In addition, the specific role played by scholars hailing from Iran—and, to a lesser extent, from Central Asia—in the juridical-religious disputes of the Indian court shows how crucial inter-Asian connections and networks were in the fashioning of Mughal ideology but also the ways in which the ongoing flow of émigré ʿulama was disciplined before being incorporated into the empire.

Sign in / Sign up

Export Citation Format

Share Document