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1.
Genet Med ; 26(4): 101059, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38158857

RESUMO

PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families. METHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts. RESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation. CONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.


Assuntos
Processamento Alternativo , Síndromes Orofaciodigitais , Masculino , Humanos , Processamento Alternativo/genética , Síndromes Orofaciodigitais/genética , Splicing de RNA , Íntrons , Spliceossomos/genética , Ribonucleoproteínas/genética
2.
Elife ; 122024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38497812

RESUMO

Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.


Assuntos
Síndrome de Down , Animais , Camundongos , Feminino , Gravidez , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Trissomia , Genitália , Cabeça , Antioxidantes , Modelos Animais de Doenças
3.
Inorg Chem ; 48(19): 9236-49, 2009 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-19746898

RESUMO

The coordination chemistry of three new quinoline pendant arm derivatives of [9]aneN(3) (L(1), L(2)) and [9]aneN(2)S (L(3)) toward Cu(II), Zn(II), Cd(II), Hg(II), and Pb(II) has been investigated both in solution and in the solid state. The protonation constants for L(1)-L(3) and stability constants with the aforementioned metal ions have been determined potentiometrically in 0.10 M NMe(4)Cl MeCN/H(2)O (1:1 v/v) solution at 298.1 +/- 0.1 K; the measured values show that Cu(II) has the highest affinity for all three ligands, followed by Zn(II), Hg(II), Pb(II), and Cd(II). For each metal ion considered, 1:1 complexes with L(1)-L(3) have also been isolated in the solid state and [Cu(L(1))](BF(4))(2) (1), [Zn(L(1))](BF(4))(2) (2), [Cd(L(1))](ClO(4))(2) (3), [Hg(L(1))](NO(3))(2) (4), [Pb(L(1))](ClO(4))(2) x MeCN (5), [Zn(2)Cl(2)(L(2))(2)](BF(4))(2) x 1/2 MeNO(2) x H(2)O (6), [Cu(L(3))](ClO(4))(2) (7), [Zn(L(3))(NO(3))]NO(3) (8), [Cd(L(3))(NO(3))(0.82)Cl(0.18)]NO(3) (9), and [Hg(L(3))](ClO(4))(2) x MeCN (10) have also been characterized by X-ray crystallography. The optical response of L(1)-L(3) to the presence of the above-mentioned metal ions has been investigated in MeCN/H(2)O (1:1 v/v) and H(2)O solutions. All three ligands show a stronger "OFF-ON" CHEF (chelation enhancement of fluorescence) effect in the Zn(II) complexes than in the Cd(II) complexes in both media. The results have been examined by considering the ratio I(rel)(Zn(II))/I(rel)(Cd(II)), within the emerging idea that the relative strength of the CHEF effect for the small Zn(II) ion as compared to larger Cd(II) ion might be determined by steric crowding in the corresponding complexes with quinoline-based fluorescent chemosensors.

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