10 research outputs found
BDNF and DYRK1A are variable and inversely correlated in lymphoblastoid cell lines from Down Syndrome patients
No full textDown syndrome or trisomy 21 is the most common genetic disorder leading to mental retardation. One feature is impaired short- and long-term spatial memory, which has been linked to altered brain-derived neurotrophic factor (BDNF) levels. Mouse models of Down syndrome have been used to assess neurotrophin levels, and reduced BDNF has been demonstrated in brains of adult transgenic mice overexpressing Dyrk1a, a candidate gene for Down syndrome phenotypes. Given the link between DYRK1A overexpression and BDNF reduction in mice, we sought to assess a similar association in humans with Down syndrome. To determine the effect of DYRK1A overexpression on BDNF in the genomic context of both complete trisomy 21 and partial trisomy 21, we used lymphoblastoid cell lines from patients with complete aneuploidy of human chromosome 21 (three copies of DYRK1A) and from patients with partial aneuploidy having either two or three copies of DYRK1A. Decreased BDNF levels were found in lymphoblastoid cell lines from individuals with complete aneuploidy as well as those with partial aneuploidies conferring three DYRK1A alleles. In contrast, lymphoblastoid cell lines from individuals with partial trisomy 21 having only two DYRK1A copies displayed increased BDNF levels. A negative correlation was also detected between BDNF and DYRK1A levels in lymphoblastoid cell lines with complete aneuploidy of human chromosome 21. This finding indicates an upward regulatory role of DYRK1A expression on BDNF levels in lymphoblastoid cell lines and emphasizes the role of genetic variants associated with psychiatric disorders.Asma Tlili, Alexander Hoischen, Clémentine Ripoll, Eva Benabou, Anne Badel, Anne Ronan, Renaud Touraine, Yann Grattau, Samantha Stora, Bregje van Bon, Bert de Vries, Björn Menten, Nele Bockaert, Joseph Gecz, Stylianos E. Antonarakis, Dominique Campion, Marie-Claude Potier, Henri Bléhaut, Jean-Maurice Delabar and Nathalie Jane
Woord vooraf. In Nele Bockaert: 'Leon Elaut. Een bevoorrecht getuige van zijn tijd'. Uitg. Vlaams Geneesheren Verbond, Antwerpen, 1997, 11-15.
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Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity
No full textItem does not contain fulltextPURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466
FOXP1-related intellectual disability syndrome : a recognisable entity
No full textBackground: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.
Methods: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.
Results: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.
Conclusions: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management
Efeitos comportamentais da microinjeção de mCPP na concha do núcleo accumbens de ratos sob restrição alimentar
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-graduação em Neurociências, Florianópolis, 2010Efeito do sistema serotonérgico sobre a ingestão de alimentos e o consumo de água, bem como nos níveis de comportamentos relacionados à ansiedade/medo em ratos submetidos à restrição parcial de alimentos. Investigação do envolvimento dos receptores serotonérgicos 5-HT1B e 5-HT2C através da administração local bilateral de mCPP na região concha do núcleo accumbens, a fim de estabelecer uma possível relação entre o comportamento de ingestão de alimentos e o comportamento de ansiedade
Mutational analysis of the highly conserved ERY motif of the thromboxane A2 receptor: Alternative role in G protein-coupled receptor signaling
No full textThe presence of highly conserved amino acid stretches in G protein-coupled receptors (GPCRs) usually predicts an important role in receptor function. Considerable attention has therefore been focused on the involvement of the highly conserved Glu-Asp-Arg-Tyr (E-DRY) motif at the cytoplasmic end of transmembrane domain 3 in the regulation of GPCR conformational states and-or the mediation of G protein activation. In the present study, we investigated the role of Glu129 and Arg130 in the ERY of thromboxane A2 receptor α (TPα) in transfected human embryonic kidney 293 cells. We show that no conservative or nonconservative substitutions of Glu129 and Arg130 generated a constitutively active TPα mutant, but a nonconservative mutation of Arg130 (R130V) yielded a mutant receptor with significantly impaired 9,11-dideoxy-9α, 11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619)-induced accumulation of inositol phosphates (IPs). This loss-of-function phenotype seems to be caused by the uncoupling of the TPα receptor from Gq, as demonstrated by the loss of high-affinity agonist binding, and not by receptor internalization, as shown by localization studies with the R130V-green fluorescent protein fusion protein. It is interesting to note that U46619-induced activation of the nonconservative E129V mutant stimulated the production of IPs with a ∼10-fold lower EC50 and a ∼2-fold higher Emax than in the wild-type receptor. Collectively, these data demonstrate that, unlike other GPCRs, mutations of Glu129 do not induce constitutive activity, whereas Arg130 is involved in G protein coupling or recognition, and they suggest the existence within class A GPCRs of at least two different subclasses that make different uses of the highly conserved E-DRY motif.Acharya S, 1996, J BIOL CHEM, V271, P25406; Alewijnse AE, 2000, MOL PHARMACOL, V57, P890; Barak LS, 2001, P NATL ACAD SCI USA, V98, P93, DOI 10.1073-pnas.011303698; Bockaert J, 1999, EMBO J, V18, P1723, DOI 10.1093-emboj-18.7.1723; Bourne HR, 1997, CURR OPIN CELL BIOL, V9, P134, DOI 10.1016-S0955-0674(97)80054-3; Burstein ES, 1998, J BIOL CHEM, V273, P24322, DOI 10.1074-jbc.273.38.24322; Capra V, 2003, EUR J PHARMACOL, V474, P149, DOI 10.1016-S0014-2999(03)02014-4; Capra V, 1998, MOL PHARMACOL, V53, P750; Chung DA, 2002, BIOCHEM BIOPH RES CO, V293, P1233, DOI 10.1016-S0006-291X(02)00357-1; COLEMAN RA, 1995, ADV PROSTAG THROMB L, V23, P283; DAngelo DD, 1996, J BIOL CHEM, V271, P6233; DELEAN A, 1978, AM J PHYSIOL, V235, pE97; DELEAN A, 1980, J BIOL CHEM, V255, P7108; Draper N, 1966, APPL REGRESSION ANAL; FRANKE RR, 1992, J BIOL CHEM, V267, P14767; Fredriksson R, 2003, MOL PHARMACOL, V63, P1256, DOI 10.1124-mol.63.6.1256; Gether U, 2000, ENDOCR REV, V21, P90, DOI 10.1210-er.21.1.90; GRYNKIEWICZ G, 1985, J BIOL CHEM, V260, P3440; Habib A, 1997, J BIOL CHEM, V272, P7191; HIRATA M, 1991, NATURE, V349, P617, DOI 10.1038-349617a0; HIRATA T, 1994, J CLIN INVEST, V94, P1662, DOI 10.1172-JCI117510; Kinsella BT, 1997, J PHARMACOL EXP THER, V281, P957; KNEZEVIC I, 1993, J BIOL CHEM, V268, P26011; Lu ZL, 1997, MOL PHARMACOL, V51, P234; Madabushi S, 2004, J BIOL CHEM, V279, P8126, DOI 10.1074-jbc.M312671200; Morin D, 1998, FEBS LETT, V441, P470, DOI 10.1016-S0014-5793(98)01585-3; MORO O, 1993, J BIOL CHEM, V268, P22273; MUNSON PJ, 1980, ANAL BIOCHEM, V107, P220, DOI 10.1016-0003-2697(80)90515-1; Parent JL, 1999, J BIOL CHEM, V274, P8941, DOI 10.1074-jbc.274.13.8941; Rasmussen SGF, 1999, MOL PHARMACOL, V56, P175; Rovati GE, 1998, TRENDS PHARMACOL SCI, V19, P365; SAMAMA P, 1993, J BIOL CHEM, V268, P4625; Scheer A, 1997, P NATL ACAD SCI USA, V94, P808, DOI 10.1073-pnas.94.3.808; Scheer A, 2000, MOL PHARMACOL, V57, P219; Scheer A, 1996, EMBO J, V15, P3566; SEUWEN K, 1988, EMBO J, V7, P161; SHENKER A, 1991, J BIOL CHEM, V266, P9309; Shibata T, 1996, BIOCHEM BIOPH RES CO, V218, P383, DOI 10.1006-bbrc.1996.0067; Wess J, 1998, PHARMACOL THERAPEUT, V80, P231, DOI 10.1016-S0163-7258(98)00030-8; Wess J, 1997, FASEB J, V11, P346; Wilbanks AM, 2002, BIOCHEMISTRY-US, V41, P11981, DOI 10.1021-bi020275m; Wong SKF, 2003, NEUROSIGNALS, V12, P1, DOI 10.1159-000068914; Zhou HP, 1999, BIOCHEM BIOPH RES CO, V264, P171, DOI 10.1006-bbrc.1999.1508; ZHU SZ, 1994, MOL PHARMACOL, V45, P51743464
Redefining the MED13L syndrome
No full textCongenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.We thank all families for participation in this study, Bettina Lipkowitz and Susanne Freier for excellent technical assistance. This work was supported by the Deutsches Humangenom-Programm (DHGP, grant number 01KW9908), the Nationales Genomforschungsnetzwerk (NGFN, project number 01GR0105), the German Research Foundation (SFB665), the Brain and Behavior Foundation (AA), the Berlin Institute of Health (BIH), the Sonnenfeld Stiftung, the Senate of Berlin by funds to the Berlin Institute for Medical Systems Biology (BIMSB), the Iranian National Science foundation, FEDER funds through the COMPETE program, Portuguese national funds through FCT - Fundacao para a Ciencia e Tecnologia (project PIC/IC/83026/2007, scholarship to FL SFRH/BD/84650/2010), the Max Planck Society and the EU FP 7 project GENCODYS (grant number 241995)
