LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 4 of total 4

Search options

  1. Article ; Online: An in vivo functional assay to characterize human STAT5B genetic variants during zebrafish development.

    Landi, Estefanía / Karabatas, Liliana / Rodríguez Gomez, Tomás / Salatino, Lucía / Scaglia, Paula / Ramírez, Laura / Keselman, Ana / Braslavsky, Débora / Sanguineti, Nora / Pennisi, Patricia / Rey, Rodolfo A / Bergadá, Ignacio / Jasper, Héctor G / Domené, Horacio M / Plazas, Paola V / Domené, Sabina

    Human molecular genetics

    2023  Volume 32, Issue 15, Page(s) 2473–2484

    Abstract: Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding ... ...

    Abstract Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and insulin-like growth factor acid-labile subunit (IGFALS). Although STAT5B deficiency was established as an autosomal recessive disorder, heterozygous dominant-negative STAT5B variants have been reported in patients with less severe growth deficit and milder immune dysfunction. We developed an in vivo functional assay in zebrafish to characterize the pathogenicity of three human STAT5B variants (p.Ala630Pro, p.Gln474Arg and p.Lys632Asn). Overexpression of human wild-type (WT) STAT5B mRNA and its variants led to a significant reduction of body length together with developmental malformations in zebrafish embryos. Overexpression of p.Ala630Pro, p.Gln474Arg or p.Lys632Asn led to an increased number of embryos with pericardial edema, cyclopia and bent spine compared with WT STAT5B. Although co-injection of WT and p.Gln474Arg and WT and p.Lys632Asn STAT5B mRNA in zebrafish embryos partially or fully rescues the length and the developmental malformations in zebrafish embryos, co-injection of WT and p.Ala630Pro STAT5B mRNA leads to a greater number of embryos with developmental malformations and a reduction in body length of these embryos. These results suggest that these variants could interfere with endogenous stat5.1 signaling through different mechanisms. In situ hybridization of zebrafish embryos overexpressing p.Gln474Arg and p.Lys632Asn STAT5B mRNA shows a reduction in igf1 expression. In conclusion, our study reveals the pathogenicity of the STAT5B variants studied.
    MeSH term(s) Animals ; Humans ; Zebrafish/genetics ; Zebrafish/metabolism ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism ; Growth Hormone ; Signal Transduction/genetics ; RNA, Messenger ; Insulin-Like Growth Factor I/genetics
    Chemical Substances STAT5 Transcription Factor ; Growth Hormone (9002-72-6) ; RNA, Messenger ; Insulin-Like Growth Factor I (67763-96-6) ; STAT5B protein, human
    Language English
    Publishing date 2023-04-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddad078
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 3469: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: Expression of acid-labile subunit (ALS) in developing and adult zebrafish and its role in dorso-ventral patterning during development.

    Landi, Estefanía / Karabatas, Liliana / Scaglia, Paula / Pisciottano, Francisco / Gutiérrez, Mariana / Ramírez, Laura / Bergadá, Ignacio / Rey, Rodolfo A / Jasper, Héctor Guillermo / Domené, Horacio Mario / Plazas, Paola Viviana / Domené, Sabina

    General and comparative endocrinology

    2020  Volume 299, Page(s) 113591

    Abstract: Mammalian acid-labile subunit (ALS) is a serum protein that binds binary complexes between Insulin-like growth factors (IGFs) and Insulin-like growth factor-binding proteins (IGFBPs) extending their half-life and keeping them in the vasculature. Human ... ...

    Abstract Mammalian acid-labile subunit (ALS) is a serum protein that binds binary complexes between Insulin-like growth factors (IGFs) and Insulin-like growth factor-binding proteins (IGFBPs) extending their half-life and keeping them in the vasculature. Human ALS deficiency (ACLSD), due to homozygous or compound heterozygous mutations in IGFALS, leads to moderate short stature with reduced levels of IGF-I and IGFBP-3. There is only one corresponding zebrafish ortholog gene and it has not yet been studied. In this study we elucidate the role of igfals during zebrafish development. In zebrafish embryos igfals mRNA is expressed throughout development, mainly in the brain and subsequently also in the gut and swimbladder. To determine its role during development, we knocked down igfals gene product using morpholinos (MOs). Igfals morphant embryos displayed dorsalization in different degrees of severity, including a shortened trunk and loss of tail. Furthermore, co-injection of human IGFALS (hIGFALS) mRNA was able to rescue the MO-induced phenotype. Finally, overexpression of either hIGFALS or zebrafish igfals (zigfals) mRNA leads to ventralization of embryos including a reduced head and enlarged tail. These findings suggest that als plays an important role in dorso-ventral patterning during zebrafish development.
    MeSH term(s) Animals ; Carrier Proteins/metabolism ; Glycoproteins/metabolism ; Mutation ; Zebrafish/growth & development
    Chemical Substances Carrier Proteins ; Glycoproteins ; insulin-like growth factor binding protein, acid labile subunit
    Language English
    Publishing date 2020-08-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1851-x
    ISSN 1095-6840 ; 0016-6480
    ISSN (online) 1095-6840
    ISSN 0016-6480
    DOI 10.1016/j.ygcen.2020.113591
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 164: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI).

    Ramírez, Laura / Sanguineti, Nora / Scaglia, Paula / Keselman, Ana / Ballerini, María Gabriela / Karabatas, Liliana / Landi, Estefanía / Castro, Julia / Domené, Sabina / Pennisi, Patricia / Jasper, Héctor / Rey, Rodolfo A / Vázquez, Martín / Domené, Horacio / Bergadá, Ignacio / Gutiérrez, Mariana

    Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society

    2019  Volume 50, Page(s) 61–70

    Abstract: Background: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I ( ... ...

    Abstract Background: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure.
    Objective: To characterize the molecular defect in a patient with short stature and partial GHI.
    Patient and methods: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed.
    Results: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency.
    Conclusions: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.
    MeSH term(s) Agammaglobulinemia/genetics ; Agammaglobulinemia/immunology ; Child, Preschool ; Heterozygote ; Human Growth Hormone/metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/metabolism ; Laron Syndrome/genetics ; Laron Syndrome/immunology ; Laron Syndrome/metabolism ; Laron Syndrome/physiopathology ; Male ; Pituitary Function Tests ; Point Mutation ; STAT5 Transcription Factor/genetics ; Severity of Illness Index
    Chemical Substances IGF1 protein, human ; IGFBP3 protein, human ; Insulin-Like Growth Factor Binding Protein 3 ; STAT5 Transcription Factor ; STAT5B protein, human ; Human Growth Hormone (12629-01-5) ; Insulin-Like Growth Factor I (67763-96-6)
    Language English
    Publishing date 2019-12-27
    Publishing country Scotland
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1436781-6
    ISSN 1532-2238 ; 1096-6374
    ISSN (online) 1532-2238
    ISSN 1096-6374
    DOI 10.1016/j.ghir.2019.12.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 3319: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency.

    Keselman, Ana Claudia / Martin, Ayelen / Scaglia, Paula Alejandra / Sanguineti, Nora María / Armando, Romina / Gutiérrez, Mariana / Braslavsky, Débora / Ballerini, María Gabriela / Ropelato, María Gabriela / Ramirez, Laura / Landi, Estefanía / Domené, Sabina / Castro, Julia F / Cassinelli, Hamilton / Casali, Bárbara / Del Rey, Graciela / Barros, Ángel Campos / Nevado Blanco, Julián / Domené, Horacio /
    Jasper, Héctor / Arberas, Claudia / Rey, Rodolfo A / Lapunzina-Badía, Pablo / Bergadá, Ignacio / Pennisi, Patricia A

    European journal of endocrinology

    2019  Volume 181, Issue 5, Page(s) K43–K53

    Abstract: Background: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe ... ...

    Abstract Background: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation.
    Results: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth.
    Conclusion: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.
    MeSH term(s) Abnormalities, Multiple/genetics ; Cell Proliferation ; Computational Biology ; Computer Simulation ; Fetal Growth Retardation/genetics ; Growth Disorders/genetics ; HEK293 Cells ; Hearing Loss, Sensorineural/genetics ; Homozygote ; Humans ; Infant ; Insulin-Like Growth Factor I/deficiency ; Insulin-Like Growth Factor I/genetics ; Male ; Mutation, Missense/genetics ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Receptor, IGF Type 1 ; Receptors, Somatomedin/genetics ; Tyrosine/genetics
    Chemical Substances IGF1 protein, human ; IGF1R protein, human ; Receptors, Somatomedin ; Tyrosine (42HK56048U) ; Insulin-Like Growth Factor I (67763-96-6) ; Receptor, IGF Type 1 (EC 2.7.10.1)
    Language English
    Publishing date 2019-09-20
    Publishing country England
    Document type Case Reports
    ZDB-ID 1183856-5
    ISSN 1479-683X ; 0804-4643
    ISSN (online) 1479-683X
    ISSN 0804-4643
    DOI 10.1530/EJE-19-0563
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.147: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top