Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking

Pasquale Piccolo,Valeria Sabatino,Pratibha Mithbaokar,Elena Polishchuck,Simon K Law,Lorena Magraner-Pardo,Tirso Pons,Roman Polishchuck,Nicola Brunetti-Pierri

doi:10.1016/j.ymgmr.2019.100504

Abstract

Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) is an autosomal disorder characterized by short-limb dwarfism, brachydactyly, cardiac valvular disease, and laryngotracheal stenosis. Mutations in ADAMTSL2, FBN1, and LTBP3 genes are responsible for this condition. We found that three previously described cases of GPHYSD diagnosed clinically were homozygote or compound heterozygotes for five ADAMTSL2 variants, four of which not being previously reported. By electron microscopy, skin fibroblasts available in one case homozygote for an ADAMTSL2 variant showed a defective intracellular localization of mutant ADAMTSL2 protein that did not accumulate within lysosome-like intra-cytoplasmic inclusions. Moreover, this mutant ADAMTSL2 protein was less secreted in medium and resulted in increased SMAD2 phosphorylation in transfected HEK293 cells.

Highlights

Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) presents with short stature, small hands and feet, cardiac valvular disease, hepatomegaly, joint contractures, and thickened skin [1,2]
The variants found in subject 1 c.2431G > A (p.Gly811Arg, rs113994124) localized in the spacer domain and c.1942C > T (p.Arg648Cys, rs1198735320) localized in the TSR3 domain are annotated in dbSNP and 1000Genomes, whereas the remaining variants including c.1943G > C (p.Arg648Pro) and c.1966G > A (p.Gly656Ser) in subject 2 both affecting TSR3, and the homozygous c.886G > A (p.Gly296Arg) variant of subject 3 affecting the spacer domain were not previously reported but they are clustered with two or more other previously reported GPHYSD-related variants on 3D models of ADAMTSL2 (Fig. 1)
All five variants are not reported in controls of the Subjects Gender ADAMTSL2 variants allele1/allele2 electron microscopy (EM) inclusions

Summary

Introduction

Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) presents with short stature, small hands and feet, cardiac valvular disease, hepatomegaly, joint contractures, and thickened skin [1,2]. GPHYSD is caused by bi-allelic mutations in a disintegrin and metalloproteinase with thrombospondin motifs-like 2 (ADAMTSL2) [3], heterozygous mutations in fibrillin-1 (FBN1) [4] or in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) [5]. Mutations in ADAMTSL2 and FBN1 affect Transforming Growth Factor-β (TGF-β) signaling [3,4] whereas no evidence of altered TGF-β signaling was detected in serum of patients carrying LTBP3 variants [5]. TGF-β is sequestered in an inactive, latent form by the extracellular matrix (ECM) through interactions with ECM proteins. Among these, ordered polymers of fibrillin play a major role, as they bind latent TGF-β and maintain TFG-β biologically inactive. ADAMTSL2 belongs to a subgroup of ADAMTS-like proteins sharing homology only with non-enzymatic domains of ADAMTS metalloproteinase [6]. ADAMTSL2 consists of a 30 amino acid signal peptide, an

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Conclusion