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A mouse model of Proteus syndrome
Marjorie J Lindhurst1, Lauren R Brinster2, Hannah C Kondolf1
1Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Human Molecular Genetics
|June 14, 2019
Summary
Proteus syndrome mouse models reveal mosaic AKT1 variant causes overgrowth disorders. Lesions like vascular malformations and cysts developed, with some cells inducing overgrowth in neighboring cells.
Area of Science:
- Genetics
- Developmental Biology
- Pathology
Background:
- Proteus syndrome is a rare mosaic overgrowth disorder.
- It is caused by somatic activating variants in the AKT1 gene.
- Clinical presentation is highly variable, affecting multiple tissue types.
Purpose of the Study:
- To develop and characterize mouse models of Proteus syndrome.
- To investigate the phenotypic consequences of mosaic AKT1 variant expression.
- To explore the cellular mechanisms underlying lesion development.
Main Methods:
- Two methods were used to create mouse models with mosaic AKT1 variant expression.
- Variant allele fractions (VAFs) were analyzed across various tissues.
- Histological analysis and GFP staining were employed to identify variant-positive cells and assess signaling.
Main Results:
- Mouse models exhibited phenotypic heterogeneity, with lesions appearing after 12 months.
- Vascular malformations (VMs) were the most common finding, followed by cysts and hyperplasia.
- Non-zero blood VAF was detected in most mice, contrasting with human patients.
- Evidence suggests non-cell autonomous effects, where variant-positive cells can induce overgrowth in neighboring cells.
Conclusions:
- Mosaic AKT1 variant expression in mice recapitulates key features of Proteus syndrome.
- Vascular malformations and cysts are prominent phenotypes.
- The study highlights the potential for non-cell autonomous mechanisms in Proteus syndrome pathogenesis.
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