ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome

Area of Science:

• Extracellular matrix biology
• Developmental biology
• Genetics

Background:

• Fibrillin microfibrils are essential for elastic tissue properties and growth factor regulation.
• A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10) plays a key role in fibrillin microfibril function.
• Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS), a disorder with diverse clinical manifestations.

Purpose of the Study:

• To investigate the role of ADAMTS10 in fibrillin microfibril assembly.
• To characterize a novel mouse model of ADAMTS10-induced Weill-Marchesani syndrome (WMS).
• To elucidate the molecular mechanisms underlying WMS pathogenesis.

Main Methods:

• Generated a WMS mouse model using CRISPR-Cas9 gene editing to introduce a patient-derived ADAMTS10 truncation mutation.
• Analyzed skeletal growth, ocular development, and skeletal muscle characteristics in homozygous WMS mice.
• Assessed gene expression profiles and intracellular signaling pathways (SMAD, MAPK) in WMS mice.

Main Results:

• Homozygous WMS mice exhibited reduced size, shortened long bones, and growth plate abnormalities.
• Ocular abnormalities included decreased ciliary processes and increased fibrillin-2 microfibrils.
• WMS mice displayed increased skeletal muscle mass, altered myogenesis, mitochondrial dysfunction, and dysregulated SMAD/MAPK signaling.

Conclusions:

• The ADAMTS10 WMS mouse model recapitulates key features of the human syndrome.
• ADAMTS10 deficiency perturbs fibrillin microfibril assembly, leading to skeletal, ocular, and muscular defects.
• This model provides a valuable tool for studying WMS pathogenesis and developing therapeutic strategies.