Mutations inLTBP3cause acromicric dysplasia and geleophysic dysplasia

Abstract

The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.

Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect

“…Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) is a connective tissue disorder presenting with short stature, small hands and feet, cardiac valvular disease, hepatomegaly, joint contractures, and thickened skin (Rosser, Wilkinson, Hurst, McGaughran, & Donnai, ; Spranger, Gilbert, Tuffli, Rossiter, & Opitz, ; Vanace, Friedman, & Wagner, ). Although initially suspected to be a lysosomal storage disorder (Lipson, Kan, & Kozlowski, ; Wraith, Bankier, Chow, Danks, & Sardharwalla, ), GPHYSD was later recognized to be caused by mutations in genes encoding components of the extracellular matrix (ECM) including a disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2, MIM612277) (GPHYSD1) (Le Goff et al, ), fibrillin 1 ( FBN1 , MIM134797) (GPHYSD2) (Le Goff et al, ), and latent transforming growth factor β (TGF‐β) binding protein 3 ( LTBP3 , MIM 602090) (GPHYSD3) (McInerney‐Leo et al, ). Transforming Growth Factor‐β (TGF‐β) is sequestered in an inactive and latent form by interactions with several ECM proteins and ordered polymers of fibrillin bind latent TGF‐β maintaining TFG‐β biologically inactive.…”

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

“…LTBP3 homozygous loss-of-function variants have been reported to cause dental abnormalities and short stature (DASS) in affected individuals between the ages of 2 and 28 years, but thoracic aortic disease has not been reported. [15][16][17][18] The proband of family TAA909 has DASS and also had multiple aortic and arterial aneurysms, including abdominal aortic aneurysm requiring surgical repair at the age of 44, aortic root dilation, and multiple visceral and peripheral arterial aneurysms at the age of 54 years (Table 1). His sisters inherited both LTBP3 variants and have DASS.…”

Optic disc swelling in acromicric and geleophysic dysplasia

“…Other eye findings reported in AD and GD include glaucoma (Saricaoglu et al, 2013;Zhang et al, 2004) and Brown syndrome (Faivre et al, 2001;McInerney-Leo et al, 2016). Zhang et al (2004) and Saricaoglu et al (2013) also observed an increased thickness of the cornea and lens.…”