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Updated: Jul 4, 2025
00:06
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
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ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia
Vladimir Camarena1, Monique M Williams2,3, Alejo A Morales1
1Dr. John T. Macdonald Foundation Department of Human Genetics.
JCI Insight
|February 1, 2024
Summary
Geleophysic dysplasia-1 (GD1) is caused by ADAMTSL2 variants, leading to cardiorespiratory issues. Impaired ADAMTSL2 secretion correlates with disease severity, as shown in cellular and mouse models.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder linked to ADAMTSL2 variants.
- Clinical manifestations range from perinatal lethality to milder adult phenotypes, including distinctive facial features, joint stiffness, short stature, and cardiorespiratory complications.
Purpose of the Study:
- To develop and characterize cellular and mouse models of GD1 based on a patient's compound heterozygous ADAMTSL2 variants (p.R61H and p.A165T).
- To investigate the genotype-phenotype correlation between ADAMTSL2 secretion impairment and disease severity.
Main Methods:
- Development of cellular and mouse models mimicking patient's ADAMTSL2 variants.
- Assessment of ADAMTSL2 secretion in vitro.
- Phenotypic characterization of mice with varying ADAMTSL2 allelic combinations, including respiratory function tests, echocardiography, MRI, and histology.
Main Results:
- Both p.R61H and p.A165T ADAMTSL2 variants impaired protein secretion, with p.A165T showing a more severe effect.
- Mouse models exhibited a spectrum of GD1 phenotypes, including lethality, mild growth impairment, and severe respiratory and cardiac dysfunction.
- Respiratory dysfunction primarily affected exhalation, with some mice developing post-obstructive pneumonia. Cardiac issues included systolic dysfunction and hypertrophic cardiomyopathy.
Conclusions:
- A strong correlation exists between the degree of impaired ADAMTSL2 secretion and the severity of GD1 phenotypes.
- The developed models are valuable tools for studying GD1 pathogenesis and exploring potential therapeutic strategies.
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