Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly

2017 ◽  
Vol 55 (3) ◽  
pp. 189-197 ◽  
Author(s):  
Esra Yıldız Bölükbaşı ◽  
Sara Mumtaz ◽  
Muhammad Afzal ◽  
Ute Woehlbier ◽  
Sajid Malik ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
In Silico ◽  
Phenotypic Variability ◽  
Cone Dystrophy ◽  
Control Group ◽  
Homozygous Mutation ◽  
Homozygous State ◽  
Bardet Biedl Syndrome ◽  
Postaxial Polydactyly ◽  
Truncating Mutation

BackgroundBardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype.MethodsSNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity.ResultsPatients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating CEP19 c.194_195insA (p.Tyr65*) mutation. We also found glioma-associated oncogene homolog 1(GLI1) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant CCDC28B c.330C>T and missense MKKS/BBS6 p.Ile339Val, and the others are C8ORF37/BBS21 p.Ala178Val and TMEM67/BBS14 modifier p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group.ConclusionCEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in GLI1, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.

Bardet-Biedl syndrome presenting with laryngeal web and bifid epiglottis

2021 ◽  
Vol 14 (1) ◽  
pp. e236325
Author(s):  
Parminder Kaur ◽  
Chakshu Chaudhry ◽  
Harsha Neelam ◽  
Inusha Panigrahi
Keyword(s):  
Cognitive Impairment ◽  
Mutation Analysis ◽  
Autosomal Recessive ◽  
Cone Dystrophy ◽  
Bardet Biedl Syndrome ◽  
Homozygous Variant ◽  
Postaxial Polydactyly ◽  
Multiple Genes ◽  
Renal Abnormalities

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by rod-cone dystrophy, obesity, postaxial polydactyly, cognitive impairment, hypogonadism, renal abnormalities, and rarely, laryngeal webs or bifid epiglottis. Most patients present with obesity. Multiple genes are involved in causation of BBS and there is also evidence of triallelic inheritance. We herein report an Asian boy who had weak cry and stridor since birth, and on evaluation was found to have both laryngeal web and bifid epiglottis. Mutation analysis revealed a homozygous variant in BBS10 gene.

scholarly journals Blood coagulation in venous thrombosis, complicating treatment of children, adolescents and young adults with lymphomas

2019 ◽  
Vol 13 (4) ◽  
pp. 37-45
Author(s):  
V. V. Dmitriev ◽  
A. S. Fedorova ◽  
N. V. Lipay ◽  
I. V. Begun ◽  
I. A. Dunaev ◽  
...  
Keyword(s):  
Young Adults ◽  
Venous Thrombosis ◽  
Hodgkin Lymphoma ◽  
Blood Coagulation ◽  
Anticoagulant Therapy ◽  
Blood Clotting ◽  
Adolescents And Young Adults ◽  
Control Group ◽  
Homozygous Mutation ◽  
Healthy Children

Objective of the study was to compare blood clotting parameters in lymphoma patients with or without venous thrombosis (VT), as well as to analyze the duration and outcome of anticoagulant therapy in children, adolescents and young adults with lymphoma, whose program treatment was complicated by VT.Materials and methods . The analysis included 28 patients with lymphoma (Hodgkin lymphoma – 5, non-Hodgkin lymphoma – 23), aged from 2 to 25 years (median – 16.0 years), whose program treatment in 2005–2017 was complicated by VT. The case-control study was carried out to compare the parameters of blood coagulation. The control group consisted of 22 patients, aged from 2 to 20 years (median – 15.5 years) with the same diagnosis, age, therapy protocol and phase of treatment who had no thrombotic complications. The comparison group consisted of 35 healthy children aged from 3 to 18 years (median – 14.0 years).Results . There was no difference in majority of blood clotting parameters in lymphoma patients with or without VT. Hyperfibrinogenemia and an increased D-dimers level distinguished patients with lymphoma, regardless of the presence or absence of thrombosis, from healthy children of the same age (р<0.05). Anticoagulant therapy up to 3 months received 10 patients, for 4–6 months – 4, for 7–12 months – 12, up to 18 months – 2. One adult patient with a homozygous mutation 20210G>A gene of the factor II takes warfarin continuously for a long time after relapse of VT. Complete recanalization of the thrombosed vessel occurred within the first 3 months in 9 patients, within 4–6 months – in 1, within 7–12 months ‒ in 4. Partial recanalization within 3–12 months was confirmed in 8 patients. Vein obliteration, mainly the internal jugular vein, as the outcome of VT occurred in 6 patients within 4–12 months.Conclusion . Detection of routine blood clotting parameters does not allow identifying patients with thrombosis among children, adolescents and young adults with lymphoma. Fibrinogen and D-dimers levels were significantly higher in lymphoma patients, than in healthy children. Anticoagulant therapy for 3–12 months led to the complete or partial recanalization of VT in 79 % of patients. To detect blood clotting parameters by thrombosis development, as well as to reveal and monitor transient and permanent risk factors are necessary to specify the cause of VT and to determine the appropriate anticoagulant therapy.

scholarly journals Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

2018 ◽  
Author(s):  
Jose Velilla ◽  
Michael Mario Marchetti ◽  
Agnes Toth-Petroczy ◽  
Claire Grosgogeat ◽  
Alexis H Bennett ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
In Silico ◽  
Muscular Atrophy ◽  
Structural Modeling ◽  
Recessive Mutation ◽  
Homozygous Mutation ◽  
Functional Studies ◽  
Whole Exome

AbstractObjectiveThe objective of this study is to identify the genetic cause of disease in a congenital form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWhole exome sequencing revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by western blot and immunohistochemical analysis show that p.S94L reduces TRPV4 protein stability because of increased cytotoxicity and therefore involves a gain-of-function mechanism.ConclusionThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of congenital spinal muscular atrophy and arthrogryposis.

scholarly journals Jaceidin Flavonoid Isolated from Chiliadenus montanus Attenuates Tumor Progression in Mice via VEGF Inhibition: In Vivo and In Silico Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1031 ◽  
Author(s):  
Sameh S. Elhady ◽  
Enas E. Eltamany ◽  
Amera E. Shaaban ◽  
Alaa A. Bagalagel ◽  
Yosra A. Muhammad ◽  
...  
Keyword(s):  
Cell Line ◽  
Cancer Cell ◽  
In Silico ◽  
Cancer Cell Line ◽  
Control Group ◽  
Phytochemical Study ◽  
Aerial Parts ◽  
In Silico Studies

Phytochemical study of Chiliadenus montanus aerial parts afforded six compounds; Intermedeol (1), 5α-hydroperoxy-β-eudesmol (2), 5,7-dihydroxy-3,3’,4’-trimethoxyflavone (3), 5,7,4’-trihydroxy-3,6,3’-trimethoxyflavone (jaceidin) (4), eudesm-11,13-ene-1β,4β,7α-triol (5) and 1β,4β,7β,11-tetrahydroxyeudesmane (6). These compounds were identified based on their NMR spectral data. The isolated compounds were tested for their cytotoxicity against liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). Jaceidin flavonoid (4) exhibited the highest cytotoxic effect in vitro. Therefore, both of jaceidin and C. montanus extract were evaluated for their in vivo anti-tumor activity against Ehrlich’s ascites carcinoma (EAC). Compared to control group, jaceidin and C. montanus extract decreased the tumor weight, improved the histological picture of tumor cells, lowered the levels of VEGF and ameliorate the oxidative stress. Molecular docking and in silico studies suggested that jaceidin was a selective inhibitor of VEGF-mediated angiogenesis with excellent membrane permeability and oral bioavailability.

scholarly journals Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism

2012 ◽  
Vol 56 (8) ◽  
pp. 540-544 ◽  
Author(s):  
Daiane Beneduzzi ◽  
Ericka B. Trarbach ◽  
Ana Claudia Latronico ◽  
Berenice Bilharinho de Mendonca ◽  
Letícia F. G. Silveira
Keyword(s):  
In Silico ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
In Silico Analysis ◽  
Control Group ◽  
Coding Region ◽  
Novel Variant ◽  
Gonadotropin Releasing Hormone Receptor ◽  
Inactivating Mutation ◽  
Silico Analysis

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4

scholarly journals Acmella oleracea (L) R. K. Jansen Reproductive Toxicity in Zebrafish: An In Vivo and In Silico Assessment

2019 ◽  
Vol 2019 ◽  
pp. 1-19 ◽  
Author(s):  
Gisele Custodio de Souza ◽  
Arlindo César Matias Pereira ◽  
Muller Duarte Viana ◽  
Adriana Maciel Ferreira ◽  
Ianna Dias Ribeiro da Silva ◽  
...  
Keyword(s):  
Embryonic Development ◽  
In Silico ◽  
Reproductive Toxicity ◽  
Control Group ◽  
The North ◽  
Significant Difference ◽  
Hydroethanolic Extract ◽  
Primary Compound ◽  
F1 Generation

The plant species Acmella oleracea L. is used in the north of Brazil for the treatment of a range of illnesses, such as tuberculosis, flu, cough, and rheumatism and as an anti-inflammatory agent; besides, hydroethanolic formulations with this species are popularly used as a female aphrodisiac agent. However, currently, there are no studies performed evaluating its effect on embryonic development. Hence, this research aimed to evaluate the effects of the hydroethanolic extract of A. oleracea (EHFAo) on the reproductive performance (parental) and embryonic development (F1 generation) of zebrafish, at concentrations of 50, 100, and 200 μg/L. Histopathology of parental gonads after 21 days of exposure to EHFAo reveals few alterations in the ovaries and testes, not impairing the reproduction; an increase of eggs deposition was observed in animals treated with EHFAo at the highest concentrations. Nevertheless, concerning the embryonic development of F1, teratogenic effects were observed including tail deformation, cardiac and yolk edema, scoliosis, and growth retardation; these alterations were more prominent in the groups born from progenitors exposed to the highest concentrations (100 and 200 μg/L.); but only the occurrence of yolk and cardiac edema had a statistically significant difference when compared to the control group. The chromatographic analysis shows that spilanthol (affinin) was the primary compound found in the EHFAo. Hence, in silico assessment was performed to evaluate the pharmacokinetic and toxicological properties of this molecule and 37 metabolites derived from it. Overall, our data show that the treatment caused no detrimental changes in progenitors regarding their gonads or fertility but caused some potentially teratogenic activity in embryos, which may be due to the action of spilanthol’s metabolites M3, M6, M7, M8, M16, M28, and M31.

scholarly journals Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

2019 ◽  
Vol 5 (2) ◽  
pp. e312 ◽  
Author(s):  
Jose Velilla ◽  
Michael Mario Marchetti ◽  
Agnes Toth-Petroczy ◽  
Claire Grosgogeat ◽  
Alexis H. Bennett ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
In Silico ◽  
Muscular Atrophy ◽  
Immunohistochemical Analysis ◽  
Structural Modeling ◽  
Recessive Mutation ◽  
Heterologous Protein Expression ◽  
Homozygous Mutation ◽  
Arthrogryposis Multiplex Congenita ◽  
Functional Studies

ObjectiveTo identify the genetic cause of disease in a form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, and diminished lower limb movement. Whole-exome sequencing (WES) was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWES revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by Western blot and immunohistochemical analysis show that p.S94L increased TRPV4 activity-based cytotoxicity and resultant decreased TRPV4 expression levels, therefore involves a gain-of-function mechanism.ConclusionsThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of CSMAA.

scholarly journals β-Carotene: A Natural Compound Improves Cognitive Impairment and Oxidative Stress in a Mouse Model of Streptozotocin-Induced Alzheimer’s Disease

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 441 ◽  
Author(s):  
Sundas Hira ◽  
Uzma Saleem ◽  
Fareeha Anwar ◽  
Muhammad Farhan Sohail ◽  
Zohaib Raza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Control Group ◽  
Enhancement Effect ◽  
Amyloid Β Protein ◽  
Group I ◽  
In Silico Studies ◽  
Β Carotene

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a cascade of changes in cognitive, behavioral, and social activities. Several areas of the brain are involved in the regulation of memory. Of most importance are the amygdala and hippocampus. Antioxidant therapy is used for the palliative treatment of different degenerative diseases like diabetes, cirrhosis, and Parkinson’s, etc. The objective of this study was to assess the effectiveness of exogenous antioxidants, in particular, β carotene (1.02 and 2.05 mg/kg) against intracerebroventricular injected streptozotocin-induced memory impairment in mice. Streptozotocin (3 mg/kg, i.c.v) was administered in two separate doses (on 1st and 3rd days of treatment) for neurodegeneration. Fifty Albino mice (male) were selected in the protocol, and they were classified into five groups (Group I—control, Group II—disease, Group III—standard, Group IV–V—β-carotene-treated) to investigate the cognitive enhancement effect of selected antioxidants. The cognitive performance was observed following the elevated plus-maze, passive avoidance, and open field paradigms. Acetylcholine esterase, β-amyloid protein, and biochemical markers of oxidative stress such as glutathione peroxidase, superoxide dismutase, and catalase were analyzed in brain homogenates. In silico activity against acetylcholinesterase (AChE) was determined by the molecular modeling of β-carotene. β-carotene at a dose of 2.05 mg/kg was found to attenuate the deleterious effects of streptozotocin-induced behavioral and biochemical impairments, including the inhibition of acetylcholinesterase activity. The in silico studies confirmed the binding capacity of β-carotene with the acetylcholinesterase enzyme. The administration of β-carotene attenuated streptozotocin-induced cognitive deficit via its anti-oxidative effects, inhibition of acetylcholinesterase, and the reduction of amyloid β-protein fragments. These results suggest that β-carotene could be useful for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

scholarly journals A Case of Hydrometrocolpos and Polydactyly

2015 ◽  
Vol 9 ◽  
pp. CMPed.S20787 ◽  
Author(s):  
Deepak Sharma ◽  
Srinivas Murki ◽  
Oleti Tejo Pratap ◽  
G.M. Irfan ◽  
Geeta Kolar
Keyword(s):  
Case Report ◽  
Retinal Degeneration ◽  
Renal Dysplasia ◽  
Mullerian Duct ◽  
Mental Impairment ◽  
Bardet Biedl Syndrome ◽  
Cardiac Anomalies ◽  
Postaxial Polydactyly ◽  
Müllerian Duct Anomaly ◽  
Stimulation Of

Neonatal hydrometrocolpos (HMC) is a rare Mullerian duct anomaly with an incidence of 0.006%. It occurs due to blockage of the vagina with accumulation of mucus secretions proximal to the obstacle. These secretions are secondary to intrauterine and postnatal stimulation of uterine and cervical glands by maternal estrogens. A triad of congenital HMC, Polydactyly, and cardiac anomalies are the cardinal features of McKusick-Kaufman syndrome, which is also known as hydrometrocolpos-polydactyly syndrome. Bardet-Biedl syndrome is a well-known combination of hypogonadism, obesity, postaxial polydactyly, renal dysplasia, retinal degeneration, and mental impairment. In this case report, we describe a neonate with HMC, Polydactyly, and hydronephrosis.

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