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ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia.

ABSTRACT: Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1.

SUBMITTER: Camarena V

PROVIDER: S-EPMC10972594 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia.

Camarena Vladimir V Williams Monique M MM Morales Alejo A AA Zafeer Mohammad F MF Kilic Okan V OV Kamiar Ali A Abad Clemer C Rasmussen Monica A MA Briski Laurence M LM Peart LéShon L Bademci Guney G Barbouth Deborah S DS Smithson Sarah S Wang Gaofeng G Shehadeh Lina A LA Walz Katherina K Tekin Mustafa M

JCI insight 20240201 5

Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 v ...[more]

PMID: 38300707

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Project description:Mutations in the secreted glycoprotein ADAMTSL2 cause recessive geleophysic dysplasia (GD) in humans and Musladin-Lueke syndrome (MLS) in dogs. GD is a severe, often lethal, condition presenting with short stature, brachydactyly, stiff skin, joint contractures, tracheal-bronchial stenosis and cardiac valve anomalies, whereas MLS is non-lethal and characterized by short stature and severe skin fibrosis. Although most mutations in fibrillin-1 (FBN1) cause Marfan syndrome (MFS), a microfibril disorder leading to transforming growth factor-β (TGFβ) dysregulation, domain-specific FBN1 mutations result in dominant GD. ADAMTSL2 has been previously shown to bind FBN1 and latent TGFβ-binding protein-1 (LTBP1). Here, we investigated mice with targeted Adamtsl2 inactivation as a new model for GD (Adamtsl2(-/-) mice). An intragenic lacZ reporter in these mice showed that ADAMTSL2 was produced exclusively by bronchial smooth muscle cells during embryonic lung development. Adamtsl2(-/-) mice, which died at birth, had severe bronchial epithelial dysplasia with abnormal glycogen-rich inclusions in bronchial epithelium resembling the cellular anomalies described previously in GD. An increase in microfibrils in the bronchial wall was associated with increased FBN2 and microfibril-associated glycoprotein-1 (MAGP1) staining, whereas LTBP1 staining was increased in bronchial epithelium. ADAMTSL2 was shown to bind directly to FBN2 with an affinity comparable to FBN1. The observed extracellular matrix (ECM) alterations were associated with increased bronchial epithelial TGFβ signaling at 17.5 days of gestation; however, treatment with TGFβ-neutralizing antibody did not correct the epithelial dysplasia. These investigations reveal a new function of ADAMTSL2 in modulating microfibril formation, and a previously unsuspected association with FBN2. Our studies suggest that the bronchial epithelial dysplasia accompanying microfibril dysregulation in Adamtsl2(-/-) mice cannot be reversed by TGFβ neutralization, and thus might be mediated by other mechanisms.

Project description:A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats-like 2 (ADAMTSL2) is a matricellular protein that interacts with latent TGF-b binding protein 1 and fibrillin-1. ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder named geleophysic dysplasia 1 (GPHYSD1, OMIM #231050), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for serine or threonine glycosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose modified TSRs are subsequently elongated to a Glucose1-3Fucose (GlcFuc) disaccharide by b3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS, OMIM #261540), which is characterized by skeletal defects similar to those of GPHYSD1. Several ADAMTSL2 TSRs have consensus sequences for C-mannosylation, and one TSR contains a sequon for N-glycosylation that overlaps with an O-fucosylation site. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used mass spectrometry to identify glycan modifications at the predicted consensus sequences. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2 knockout but not in B3GLCT knockout cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients lacking B3GLCT. In contrast, secretion of mouse ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6) was significantly reduced in HEK293T cells. Moreover, S641L eliminated O-fucosylation of TSR3. Combined these results provide strong evidence that developmental abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

Dataset Information

ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia.

Publications

ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia.

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