The Pathogenic ADAMTSL2 D167N Variant Causes Geleophysic Dysplasia-Like Connective Tissue Changes in Mice.

Geleophysic dysplasia (GD) is caused by recessive mutations in ADAMTSL2 (a disintegrin and metalloprotease with thrombospondin type I motifs-2; GD1), or dominant mutations in FBN1 (GD2) or LTBP3 (GD3). GD is characterized by severe short stature and other skeletal abnormalities, characteristic facial features, thick skin, and hypermuscular build. Life-threatening complications can arise from progressive heart valve disease and narrowing of the large airways, resulting in approximately 33% mortality before the age of 5 years. Despite high childhood mortality and significant morbidity, no disease-modifying treatments exist for GD. To model disease progression and enable efficacy testing of mechanism-based therapeutic approaches, a mouse model for severe GD1 was generated by introducing the patient-specific ADAMTSL2 c.499G>A (p.D167N) mutation into the mouse Adamtsl2 locus. Homozygous Adamtsl2D167N/D167N (D167N) mice had reduced postnatal survival and developed short stature. Radiographs demonstrated significantly shortened hind limb and forelimb bones with delayed mineralization and abnormally shaped vertebrae. Histologic investigation revealed a shortened growth plate, suggesting abnormalities in chondrogenesis. Cardiac histomorphometry revealed dysplastic aortic heart valves, consistent with progressive heart valve disease observed in patients with GD1. In the lungs, bronchial obstruction was observed, as previously reported for global Adamtsl2 knockout mice, likely resulting in occlusion of the affected airways. Thus, the ADAMTSL2 D167N mouse model recapitulates key clinical manifestations of patients with GD1.