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Article: Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen-Kolk syndrome.

Correa Brito, Lourdes / Keselman, Ana / Villegas, Florencia / Scaglia, Paula / Esnaola Azcoiti, María / Castro, Sebastián / Sanguineti, Nora / Izquierdo, Agustín / Maier, Marianela / Bergadá, Ignacio / Arberas, Claudia / Rey, Rodolfo A / Ropelato, María Gabriela

Frontiers in genetics

2024 Volume 15, Page(s) 1354715

Abstract: Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with ... ...

Abstract	Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with Witteveen-Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing
Language	English
Publishing date	2024-03-11
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2024.1354715
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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
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Article ; Online: Síndrome de osteoporosis-pseudoglioma: a propósito de un caso pediátrico de osteoporosis primaria.

Braslavsky, Débora / Scaglia, Paula / Sanguineti, Nora / Aza-Carmona, Miriam / Nevado Blanco, Julián / Lapunzina Badia, Pablo D / Fernández, María Del C / Ruiz, Olivia / Carmona, Alejandra / Szlago, Marina / Arberas, Claudia / Cassinelli, Hamilton / Heath, Karen / Rey, Rodolfo / Bergadá, Ignacio

Archivos argentinos de pediatria

2020 Volume 118, Issue 3, Page(s) e300–e304

Abstract: Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. ... ...

Title translation	Osteoporosis-pseudoglioma Syndrome: a pediatric case of primary osteoporosis.
Abstract	Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. Its association with congenital retinal folds should guide the diagnosis to the Osteoporosis-Pseudoglioma syndrome (OMIM 259770), a rare disease (prevalence of 1/2 000 000), caused by the loss of function of the protein LRP5 (low-density lipoprotein receptor-related protein 5) resulting in the alteration of the Wnt/β-catenin signalling pathway. We report the case of a child with congenital retinal folds, progressive loss of vision and multiple fractures whose clinical, biochemical and genetic studies confirmed the diagnosis of primary osteoporosis due to a novel homozygous inactivating variant in LRP5.
MeSH term(s)	Child ; Genetic Markers ; Genetic Testing ; Homozygote ; Humans ; Low Density Lipoprotein Receptor-Related Protein-5/genetics ; Male ; Mutation ; Osteogenesis Imperfecta/diagnosis ; Osteogenesis Imperfecta/genetics
Chemical Substances	Genetic Markers ; LRP5 protein, human ; Low Density Lipoprotein Receptor-Related Protein-5
Language	Spanish
Publishing date	2020-06-12
Publishing country	Argentina
Document type	Case Reports ; Journal Article
ZDB-ID	424449-7
ISSN	1668-3501 ; 0325-0075 ; 0004-0487
ISSN (online)	1668-3501
ISSN	0325-0075 ; 0004-0487
DOI	10.5546/aap.2020.e300
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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
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Article ; Online: p.R209H GH1 variant challenges short stature assessment.

Sanguineti, Nora / Braslavsky, Debora / Scaglia, Paula A / Keselman, Ana / Ballerini, Maria G / Ropelato, Maria G / Suco, Sofia / Vishnopolska, Sebastian / Berenstein, Ariel J / Jasper, Héctor / Domené, Horacio M / Rey, Rodolfo A / Pérez Millán, Maria I / Camper, Sally A / Bergadá, Ignacio

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

2019 Volume 50, Page(s) 23–26

Abstract: Objective: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive.: Design: We describe a non- ... ...

Abstract	Objective: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. Design: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. Results: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. Conclusions: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).
MeSH term(s)	Adolescent ; Adult ; Argentina ; Body Height ; Child ; Child, Preschool ; Diagnostic Techniques, Endocrine ; Dwarfism, Pituitary/genetics ; Dwarfism, Pituitary/metabolism ; Dwarfism, Pituitary/physiopathology ; Female ; Growth Disorders/genetics ; Growth Disorders/metabolism ; Growth Disorders/physiopathology ; Heterozygote ; Homozygote ; Human Growth Hormone/genetics ; Human Growth Hormone/metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/metabolism ; Male ; Middle Aged ; Mutation, Missense ; Pedigree ; Young Adult
Chemical Substances	IGF1 protein, human ; IGFBP3 protein, human ; Insulin-Like Growth Factor Binding Protein 3 ; Human Growth Hormone (12629-01-5) ; Insulin-Like Growth Factor I (67763-96-6)
Language	English
Publishing date	2019-12-03
Publishing country	Scotland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.2019.11.002
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Article: Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations

Gutiérrez, Mariana / Scaglia, Paula / Keselman, Ana / Martucci, Lucía / Karabatas, Liliana / Domené, Sabina / Martin, Ayelen / Pennisi, Patricia / Blanco, Miguel / Sanguineti, Nora / Bezrodnik, Liliana / Di Giovanni, Daniela / Caldirola, María Soledad / Azcoiti, María Esnaola / Gaillard, María Isabel / Denson, Lee A / Zhang, Kejian / Husami, Ammar / Yayah Jones, Nana-Hawa /

Hwa, Vivian / Revale, Santiago / Vázquez, Martín / Jasper, Héctor / Kumar, Ashish / Domené, Horacio

Molecular and cellular endocrinology. 2018 Sept. 15, v. 473

2018

Abstract: Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p ... ...

Abstract	Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms.
Keywords	autoimmune diseases ; dephosphorylation ; gain-of-function mutation ; germ cells ; growth retardation ; heterozygosity ; insulin-like growth factor I ; interleukin-6 ; patients ; signal transduction ; somatotropin ; transcription (genetics)
Language	English
Dates of publication	2018-0915
Size	p. 166-177.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2018.01.016
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Article ; Online: Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations.

Hwa, Vivian / Revale, Santiago / Vázquez, Martín / Jasper, Héctor / Kumar, Ashish / Domené, Horacio

Molecular and cellular endocrinology

2018 Volume 473, Page(s) 166–177

Abstract	Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms.
MeSH term(s)	Amino Acid Sequence ; Child, Preschool ; Female ; Germ Cells/metabolism ; Growth Disorders/genetics ; HEK293 Cells ; Hearing Loss, Sensorineural/genetics ; Human Growth Hormone/pharmacology ; Humans ; Immune System Diseases/genetics ; Infant ; Infant, Newborn ; Insulin-Like Growth Factor I/deficiency ; Insulin-Like Growth Factor I/genetics ; Interleukin-5/metabolism ; Luciferases/metabolism ; Male ; Models, Molecular ; Mutation/genetics ; Phosphorylation/drug effects ; Protein Multimerization ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; STAT3 Transcription Factor/chemistry ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; STAT5 Transcription Factor/metabolism ; Suppressor of Cytokine Signaling 3 Protein/genetics ; Suppressor of Cytokine Signaling 3 Protein/metabolism ; Transcription, Genetic/drug effects ; Exome Sequencing
Chemical Substances	Interleukin-5 ; RNA, Messenger ; SOCS3 protein, human ; STAT3 Transcription Factor ; STAT5 Transcription Factor ; STAT5B protein, human ; Suppressor of Cytokine Signaling 3 Protein ; Human Growth Hormone (12629-01-5) ; Insulin-Like Growth Factor I (67763-96-6) ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2018-02-03
Publishing country	Ireland
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2018.01.016
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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
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