{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T12:20:57Z","timestamp":1781871657886,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ben-Gurion University of the Negev, Faculty of Health Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Weill\u2013Marchesani syndrome (WMS) is a rare genetic inherited disorder with autosomal recessive and dominant modes of inheritance. WMS is characterized by the association of short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia and ectopia of the lenses, and, occasionally, heart defects. We investigated the genetic cause of a unique and novel presentation of heart-developed membranes in the supra-pulmonic, supramitral, and subaortic areas, creating stenosis that recurred after their surgical resection in four patients from one extended consanguineous family. The patients also presented ocular findings consistent with Weill\u2013Marchesani syndrome (WMS). We used whole exome sequencing (WES) to identify the causative mutation and report it as a homozygous nucleotide change c. 232T&gt;C causing p. Tyr78His in ADAMTS10. ADAMTS10 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 10) is a member of a family of zinc-dependent extracellular matrix protease family. This is the first report of a mutation in the pro-domain of ADAMTS10. The novel variation replaces a highly evolutionary conserved tyrosine with histidine. This change may affect the secretion or function of ADAMTS10 in the extracellular matrix. The compromise in protease activity may thus cause the unique presentation of the developed membranes in the heart and their recurrence after surgery.<\/jats:p>","DOI":"10.3390\/ijms24108864","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T02:04:05Z","timestamp":1684289045000},"page":"8864","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Novel Mutation in the ADAMTS10 Associated with Weil\u2013Marchesani Syndrome with a Unique Presentation of Developed Membranes Causing Severe Stenosis of the Supra Pulmonic, Supramitral, and Subaortic Areas in the Heart"],"prefix":"10.3390","volume":"24","author":[{"given":"Aviva","family":"Levitas","sequence":"first","affiliation":[{"name":"Department of Pediatric Cardiology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Aspit","sequence":"additional","affiliation":[{"name":"The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"},{"name":"The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neta","family":"Lowenthal","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Shaki","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Krymko","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9629-1276","authenticated-orcid":false,"given":"Leonel","family":"Slanovic","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronit","family":"Yagev","sequence":"additional","affiliation":[{"name":"Ophthalmology Department, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0656-3096","authenticated-orcid":false,"given":"Ruti","family":"Parvari","sequence":"additional","affiliation":[{"name":"The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"},{"name":"The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2019.11.001","article-title":"A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix","volume":"88","author":"Karoulias","year":"2020","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1086\/425231","article-title":"ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome","volume":"75","author":"Dagoneau","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1007\/s00018-011-0780-9","article-title":"Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: A novel mechanism influencing microfibril assembly and function","volume":"68","author":"Hubmacher","year":"2011","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1034\/j.1600-0420.1998.760524.x","article-title":"Ciliary body is not hyperplastic in Weill-Marchesani syndrome","volume":"76","author":"Dietlein","year":"1998","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1034\/j.1600-0420.2003.00129.x","article-title":"Chronic angle closure glaucoma secondary to frail zonular fibres and spherophakia","volume":"81","author":"Asaoka","year":"2003","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17156","DOI":"10.1074\/jbc.M111.231571","article-title":"ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts","volume":"286","author":"Kutz","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_7","unstructured":"Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). GeneReviews\u00ae, University of Washington."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/humu.22105","article-title":"LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix","volume":"33","author":"Paylakhi","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_9","first-page":"952543","article-title":"Retinal vascular tortuosity in a patient with weill-marchesani syndrome","volume":"2011","author":"Gallagher","year":"2011","journal-title":"Case Rep. Ophthalmol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.ajhg.2009.09.011","article-title":"Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature","volume":"85","author":"Morales","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sengle, G., Tsutsui, K., Keene, D.R., Tufa, S.F., Carlson, E.J., Charbonneau, N.L., Ono, R.N., Sasaki, T., Wirtz, M.K., and Samples, J.R. (2012). Microenvironmental regulation by fibrillin-1. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002425"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"037283","DOI":"10.1242\/dmm.037283","article-title":"Targeted deletion of fibrillin-1 in the mouse eye results in ectopia lentis and other ocular phenotypes associated with Marfan syndrome","volume":"12","author":"Jones","year":"2019","journal-title":"Dis. Models Mech."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1007\/s00439-002-0689-3","article-title":"Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3-p13.2","volume":"110","author":"Faivre","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1002\/ajmg.a.31861","article-title":"Cardiac findings in Weill-Marchesani syndrome","volume":"143","author":"Kojuri","year":"2007","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1002\/ajmg.a.36044","article-title":"Missense mutations in FBN1 exons 41 and 42 cause Weill-Marchesani syndrome with thoracic aortic disease and Marfan syndrome","volume":"161a","author":"Cecchi","year":"2013","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1002\/ajmg.a.38353","article-title":"Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill-Marchesani syndrome","volume":"173","author":"Newell","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Alsalem, A.B., Halees, A.S., Anazi, S., Alshamekh, S., and Alkuraya, F.S. (2013). Autozygome sequencing expands the horizon of human knockout research and provides novel insights into human phenotypic variation. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1004030"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.matbio.2015.05.004","article-title":"ADAMTS proteins as modulators of microfibril formation and function","volume":"47","author":"Hubmacher","year":"2015","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1042\/BJ20040424","article-title":"The ADAMTS metalloproteinases","volume":"386","author":"Porter","year":"2005","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1038\/ejhg.2014.264","article-title":"Identification and molecular characterisation of a homozygous missense mutation in the ADAMTS10 gene in a patient with Weill-Marchesani syndrome","volume":"23","author":"Steinkellner","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1002\/humu.20797","article-title":"Functional analysis of an ADAMTS10 signal peptide mutation in Weill-Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme","volume":"29","author":"Kutz","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.icvts.2004.04.004","article-title":"Two patients with Weill-Marchesani syndrome and mitral stenosis","volume":"3","author":"Bogers","year":"2004","journal-title":"Interact. Cardiovasc. Thorac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1093\/hmg\/ddy276","article-title":"ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome","volume":"27","author":"Mularczyk","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3389\/fcvm.2018.00122","article-title":"Discrete Subaortic Stenosis: Perspective Roadmap to a Complex Disease","volume":"5","author":"Shar","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20190893","DOI":"10.1098\/rsif.2019.0893","article-title":"The role of stress concentration in calcified bicuspid aortic valve","volume":"17","author":"Qin","year":"2020","journal-title":"J. R. Soc. Interface"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1007\/s00246-021-02545-w","article-title":"Supravalvular and Valvular Pulmonary Stenosis: Predictive Features and Responsiveness to Percutaneous Dilation","volume":"42","author":"Poupart","year":"2021","journal-title":"Pediatr. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41572-021-00276-z","article-title":"Williams syndrome","volume":"7","author":"Kozel","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"a036723","DOI":"10.1101\/cshperspect.a036723","article-title":"The Endocardium and Heart Valves","volume":"12","author":"Dye","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1053\/j.pcsu.2012.01.011","article-title":"Congenital mitral valve stenosis: Anatomic variants and surgical reconstruction","volume":"15","author":"Baird","year":"2012","journal-title":"Semin. Thorac. Cardiovasc. Surg. Pediatr. Card. Surg. Annu."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Karoulias, S.Z., Taye, N., Stanley, S., and Hubmacher, D. (2020). The ADAMTS\/Fibrillin Connection: Insights into the Biological Functions of ADAMTS10 and ADAMTS17 and Their Respective Sister Proteases. Biomolecules, 10.","DOI":"10.3390\/biom10040596"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/bdrc.20063","article-title":"Proteases in eye development and disease","volume":"78","author":"Wride","year":"2006","journal-title":"Birth Defects Res. Part C Embryo Today Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35956","DOI":"10.1038\/srep35956","article-title":"ADAMTS-10 and -6 differentially regulate cell-cell junctions and focal adhesions","volume":"6","author":"Cain","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13059-018-1457-6","article-title":"Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6","volume":"19","author":"Prins","year":"2018","journal-title":"Genome Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41588-019-0536-2","article-title":"Loss of ADAMTS19 causes progressive non-syndromic heart valve disease","volume":"52","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7227","DOI":"10.1093\/hmg\/ddv423","article-title":"PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction","volume":"24","author":"Muhammad","year":"2015","journal-title":"Hum. Mol. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8864\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:36:20Z","timestamp":1760124980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8864"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108864"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108864","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,16]]}}}