Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome
Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 protein expression and nuclear localization were assessed. Two Hmga2-knockin mouse models were generated. Five clinical SRS patients harbored HMGA2 variants with differing functional impacts: 2 stop-gain nonsense variants (c.49G>T, c.52C>T), c.166A>G missense variant, and 2 frameshift variants (c.144delC, c.145delA) leading to an identical, extended-length protein. Phenotypic features were highly variable. Nuclear localization was reduced/absent for all variants except c.166A>G. Homozygous knockin mice recapitulating the c.166A>G variant (Hmga2K56E) exhibited a growth-restricted phenotype. An Hmga2Ter76-knockin mouse model lacked detectable full-length Hmga2 protein, similarly to patient 3 and 5 variants. These mice were infertile, with a pygmy phenotype. We report a heterogeneous group of individuals with SRS harboring variants in HMGA2 and describe the first Hmga2 missense knockin mouse model (Hmga2K56E) to our knowledge causing a growth-restricted phenotype. In patients with clinical features of SRS but negative genetic screening, HMGA2 should be included in next-generation sequencing testing approaches.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
JCI insight - 9(2024), 6 vom: 20. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Maharaj, Avinaash V [VerfasserIn] |
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| Links: |
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| Themen: |
Endocrinology |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 04.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.169425 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM370064674 |
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| 520 | |a Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 protein expression and nuclear localization were assessed. Two Hmga2-knockin mouse models were generated. Five clinical SRS patients harbored HMGA2 variants with differing functional impacts: 2 stop-gain nonsense variants (c.49G>T, c.52C>T), c.166A>G missense variant, and 2 frameshift variants (c.144delC, c.145delA) leading to an identical, extended-length protein. Phenotypic features were highly variable. Nuclear localization was reduced/absent for all variants except c.166A>G. Homozygous knockin mice recapitulating the c.166A>G variant (Hmga2K56E) exhibited a growth-restricted phenotype. An Hmga2Ter76-knockin mouse model lacked detectable full-length Hmga2 protein, similarly to patient 3 and 5 variants. These mice were infertile, with a pygmy phenotype. We report a heterogeneous group of individuals with SRS harboring variants in HMGA2 and describe the first Hmga2 missense knockin mouse model (Hmga2K56E) to our knowledge causing a growth-restricted phenotype. In patients with clinical features of SRS but negative genetic screening, HMGA2 should be included in next-generation sequencing testing approaches | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Endocrinology | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Growth factors | |
| 650 | 4 | |a Molecular genetics | |
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| 700 | 1 | |a Cottrell, Emily |e verfasserin |4 aut | |
| 700 | 1 | |a Thanasupawat, Thatchawan |e verfasserin |4 aut | |
| 700 | 1 | |a Joustra, Sjoerd D |e verfasserin |4 aut | |
| 700 | 1 | |a Triggs-Raine, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Fujimoto, Masanobu |e verfasserin |4 aut | |
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| 700 | 1 | |a Clement-de Boers, Agnes |e verfasserin |4 aut | |
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