Abstract
Geleophysic Dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTSL2 variants. It is characterized by distinctive facial features, limited joint mobility, short stature with brachydactyly, and the potential for life-threatening cardiovascular and respiratory complications. The clinical spectrum spans from perinatal lethality to milder phenotypes in adult survivors, manifesting a clinical heterogeneity. The Adamtsl2-/- mouse model dies perinatally and hinders further functional investigation. In this study, we developed and characterized cellular and mouse models, which were designed to replicate the genetic profile of a patient who is compound heterozygous for two ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but notably, p.A165T exhibited a more severe impact. We conducted a thorough analysis of mice carrying different allelic combinations, including knockout, p.R61H, and p.A165T variants. This examination revealed a wide spectrum of phenotypic severity, spanning from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. While they survived, the homozygous and hemizygous p.A165T mice displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affects the expiration phase without significant fibrosis in the lungs. Evidence of microscopic post-obstructive pneumonia was found in some hemizygous and homozygous p.A165T. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction in the size of the aortic root. Histological examinations further confirmed the presence of hypertrophic cardiomyopathy with myocyte hypertrophy. In addition, evidence of elevated proteoglycan staining in the myocardium, chondroid metaplasia, along with patchy mild interstitial fibrosis within the myocardium was seen in hemizygous and homozygous p.A165T. In conclusion, our study revealed a significant correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1. The surviving mouse models we developed have provided valuable insights into the pathogenesis of GD and hold promise as valuable tools for informing and guiding future therapeutic interventions aimed at managing this disorder effectively.
