A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI).
Agammaglobulinemia
/ genetics
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
Male
Pituitary Function Tests
Point Mutation
STAT5 Transcription Factor
/ genetics
Severity of Illness Index
Growth hormone insensitivity
IGFALS
STAT5B
Whole-exome analysis
Journal
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society
ISSN: 1532-2238
Titre abrégé: Growth Horm IGF Res
Pays: Scotland
ID NLM: 9814320
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
05
11
2019
revised:
13
12
2019
accepted:
26
12
2019
pubmed:
7
1
2020
medline:
17
3
2021
entrez:
7
1
2020
Statut:
ppublish
Résumé
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. To characterize the molecular defect in a patient with short stature and partial GHI. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31902742
pii: S1096-6374(19)30062-0
doi: 10.1016/j.ghir.2019.12.005
pii:
doi:
Substances chimiques
IGF1 protein, human
0
IGFBP3 protein, human
0
Insulin-Like Growth Factor Binding Protein 3
0
STAT5 Transcription Factor
0
STAT5B protein, human
0
Human Growth Hormone
12629-01-5
Insulin-Like Growth Factor I
67763-96-6
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
61-70Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.