5 research outputs found
Detrimental effects of individual versus combined exposure to tetrabromobisphenol A and polystyrene nanoplastics in fish cell lines
The potential interactions between the diverse pollutants that can be released into the environment and the
resulting outcomes are a challenging issue that needs to be further examined. This in vitro study was aimed to
assess potential toxic effects caused by combined exposure to tetrabromobisphenol A, a flame retardant widely
used and frequently detected in aquatic matrices, and commercially available polystyrene nanoparticles as
reference material to evaluate nanoplastics risks. Our results, using freshwater fish cell lines and a set of relevant
cytotoxicity endpoints including cell viability, oxidative stress, and DNA damage, provide additional mechanistic
insights that could help to fully characterize the toxicity profiles of tetrabromobisphenol A and polystyrene
nanoparticles. Furthermore, we describe subtle changes in cell viability as well as the generation of oxidative
DNA damage after coexposure to subcytotoxic concentrations of the tested pollutantsThis work was funded by the Spanish Ministry of Science, Innovation
and Universities / Spanish State Research Agency / _RTI2018â096046-
B-C22. PSB has benefited from a contract from the Office of Education
and Research of the Community of Madrid and the European Social Fund
(PEJ-2019-AI/SAL-12775
Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B
ECEMC Working Group on Polydactyly: et al.Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAPâB corresponding to a more rudimentary extraâdigit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAPâA, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNAâbinding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAPâA/B.This study was supported by a grant from the Spanish Ministry of Economy and Competitiveness (SAF2016â75434âR) to V.L. RâP and by funding from Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science, Innovation and Universities and the FundaciĂłn 1000 sobre Defectos CongĂ©nitos to E. BâS.Peer reviewe
Common atrium/atrioventricular canal defect and postaxial polydactyly: A mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene
Clinical expression of Ellisâvan Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical spliceâsite inâframe change (c.1316â7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patientâderived fibroblasts and Evcâ/â mouse embryonic fibroblasts showed that p.Arg622Ter is a lossâofâfunction mutation, whereas p.Arg663Pro and the spliceâsite change c.1316â7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as âcommon atrium/AVCD with postaxial polydactylyâ is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotypeâphenotype correlations in this syndrome.This study was supported by funding from the Italian Ministry of Health (RCâ2019) to Alessandro De Luca, Fondazione Bambino GesĂč (Vite Coraggiose) to Marco Tartaglia, and the Spanish Ministry of Science, Innovation and Universities to Victor L. RuizâPerez (SAF2016â75434âR (AEI/FEDER, UE) and PID2019â105620RBâI00/AEI/10.13039/501100011033)
Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B
Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B
Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome
PRKACA and PRKACB code for two catalytic subunits (Cα and CÎČ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and CÎČ subunits of PKA during human development.This work was partially supported by funding from the Spanish Ministry of Science, Innovation and Universities (SAF2016-75434-R [AEI/FEDER, UE] and PID2019-105620RB-I00/AEI/10.13039/501100011033) to V.L.R.-P. S.S.T. was supported by NIH grant R03TR002947, E.M.F.M. by Kassel graduate school âClocksâ, and A.D.L. by the Italian Ministry of Health (RC-2019). The University of Antwerp supported G.M. and W.V.H. with Methusalem funding (FFB190208) and S.P. with a predoctoral grant. E.B. was supported by The Research Foundation Flanders with a postdoctoral grant (12A3814N). The study was also funded by a National Health and Medical Research Council Program Grant (1091593) to I.E.S., a Practitioner Fellowship (1006110) to I.E.S., a Senior Research Fellowship (1102971) to M.B., and an R.D. Wright Career Development Fellowship (1063799) to M.S.H. B.S.S. and G.L. were supported by Throne Holst Foundation UiO (2019-2021) and Strategic PhD fund by UiO/IMB