ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia

Autores
Camarena, Vladimir; Williams, Monique M.; Morales, Alejo A.; Zafeer, Mohammad F.; Kilic, Okan V.; Kamiar, Ali; Abad, Clemer; Rasmussen, Monica A.; Briski, Laurence M.; Peart, LéShon; Bademci, Guney; Barbouth, Deborah S.; Smithson, Sarah; Wang, Gaofeng; Shehadeh, Lina A.; Walz, Katherina; Tekin, Mustafa
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Camarena, Vladimir. University of Miami; Estados Unidos
Fil: Williams, Monique M.. No especifíca;
Fil: Morales, Alejo A.. University of Miami; Estados Unidos
Fil: Zafeer, Mohammad F.. University of Miami; Estados Unidos
Fil: Kilic, Okan V.. University of Miami; Estados Unidos
Fil: Kamiar, Ali. University of Miami; Estados Unidos
Fil: Abad, Clemer. University of Miami; Estados Unidos
Fil: Rasmussen, Monica A.. University of Miami; Estados Unidos
Fil: Briski, Laurence M.. University of Miami; Estados Unidos
Fil: Peart, LéShon. University of Miami; Estados Unidos
Fil: Bademci, Guney. University of Miami; Estados Unidos
Fil: Barbouth, Deborah S.. University of Miami; Estados Unidos
Fil: Smithson, Sarah. University of Miami; Estados Unidos
Fil: Wang, Gaofeng. University of Miami; Estados Unidos
Fil: Shehadeh, Lina A.. University of Miami; Estados Unidos
Fil: Walz, Katherina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Tekin, Mustafa. University of Miami; Estados Unidos
Materia
EXTRACELLULAR MATRIX
GD
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/276370
Acceder
id CONICETDig_01de54776fbe810d2f9c4cbd2d2069c8
oai_identifier_str oai:ri.conicet.gov.ar:11336/276370
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling ADAMTSL2 mutations determine the phenotypic severity in Geleophysic DysplasiaCamarena, VladimirWilliams, Monique M.Morales, Alejo A.Zafeer, Mohammad F.Kilic, Okan V.Kamiar, AliAbad, ClemerRasmussen, Monica A.Briski, Laurence M.Peart, LéShonBademci, GuneyBarbouth, Deborah S.Smithson, SarahWang, GaofengShehadeh, Lina A.Walz, KatherinaTekin, MustafaEXTRACELLULAR MATRIXGDhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Geleophysic 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.Fil: Camarena, Vladimir. University of Miami; Estados UnidosFil: Williams, Monique M.. No especifíca;Fil: Morales, Alejo A.. University of Miami; Estados UnidosFil: Zafeer, Mohammad F.. University of Miami; Estados UnidosFil: Kilic, Okan V.. University of Miami; Estados UnidosFil: Kamiar, Ali. University of Miami; Estados UnidosFil: Abad, Clemer. University of Miami; Estados UnidosFil: Rasmussen, Monica A.. University of Miami; Estados UnidosFil: Briski, Laurence M.. University of Miami; Estados UnidosFil: Peart, LéShon. University of Miami; Estados UnidosFil: Bademci, Guney. University of Miami; Estados UnidosFil: Barbouth, Deborah S.. University of Miami; Estados UnidosFil: Smithson, Sarah. University of Miami; Estados UnidosFil: Wang, Gaofeng. University of Miami; Estados UnidosFil: Shehadeh, Lina A.. University of Miami; Estados UnidosFil: Walz, Katherina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Tekin, Mustafa. University of Miami; Estados UnidosAmerican Society for Clinical Investigation2024-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/276370Camarena, Vladimir; Williams, Monique M.; Morales, Alejo A.; Zafeer, Mohammad F.; Kilic, Okan V.; et al.; ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia; American Society for Clinical Investigation; JCI Insight; 2-2024; 1-202379-3708CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://insight.jci.org/articles/view/174417info:eu-repo/semantics/altIdentifier/doi/10.1172/jci.insight.174417info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T14:38:39Zoai:ri.conicet.gov.ar:11336/276370instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-12-23 14:38:39.431CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
title ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
spellingShingle ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
Camarena, Vladimir
EXTRACELLULAR MATRIX
GD
title_short ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
title_full ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
title_fullStr ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
title_full_unstemmed ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
title_sort ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia
dc.creator.none.fl_str_mv Camarena, Vladimir
Williams, Monique M.
Morales, Alejo A.
Zafeer, Mohammad F.
Kilic, Okan V.
Kamiar, Ali
Abad, Clemer
Rasmussen, Monica A.
Briski, Laurence M.
Peart, LéShon
Bademci, Guney
Barbouth, Deborah S.
Smithson, Sarah
Wang, Gaofeng
Shehadeh, Lina A.
Walz, Katherina
Tekin, Mustafa
author Camarena, Vladimir
author_facet Camarena, Vladimir
Williams, Monique M.
Morales, Alejo A.
Zafeer, Mohammad F.
Kilic, Okan V.
Kamiar, Ali
Abad, Clemer
Rasmussen, Monica A.
Briski, Laurence M.
Peart, LéShon
Bademci, Guney
Barbouth, Deborah S.
Smithson, Sarah
Wang, Gaofeng
Shehadeh, Lina A.
Walz, Katherina
Tekin, Mustafa
author_role author
author2 Williams, Monique M.
Morales, Alejo A.
Zafeer, Mohammad F.
Kilic, Okan V.
Kamiar, Ali
Abad, Clemer
Rasmussen, Monica A.
Briski, Laurence M.
Peart, LéShon
Bademci, Guney
Barbouth, Deborah S.
Smithson, Sarah
Wang, Gaofeng
Shehadeh, Lina A.
Walz, Katherina
Tekin, Mustafa
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv EXTRACELLULAR MATRIX
GD
topic EXTRACELLULAR MATRIX
GD
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Camarena, Vladimir. University of Miami; Estados Unidos
Fil: Williams, Monique M.. No especifíca;
Fil: Morales, Alejo A.. University of Miami; Estados Unidos
Fil: Zafeer, Mohammad F.. University of Miami; Estados Unidos
Fil: Kilic, Okan V.. University of Miami; Estados Unidos
Fil: Kamiar, Ali. University of Miami; Estados Unidos
Fil: Abad, Clemer. University of Miami; Estados Unidos
Fil: Rasmussen, Monica A.. University of Miami; Estados Unidos
Fil: Briski, Laurence M.. University of Miami; Estados Unidos
Fil: Peart, LéShon. University of Miami; Estados Unidos
Fil: Bademci, Guney. University of Miami; Estados Unidos
Fil: Barbouth, Deborah S.. University of Miami; Estados Unidos
Fil: Smithson, Sarah. University of Miami; Estados Unidos
Fil: Wang, Gaofeng. University of Miami; Estados Unidos
Fil: Shehadeh, Lina A.. University of Miami; Estados Unidos
Fil: Walz, Katherina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Tekin, Mustafa. University of Miami; Estados Unidos
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/276370
Camarena, Vladimir; Williams, Monique M.; Morales, Alejo A.; Zafeer, Mohammad F.; Kilic, Okan V.; et al.; ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia; American Society for Clinical Investigation; JCI Insight; 2-2024; 1-20
2379-3708
CONICET Digital
CONICET
url http://hdl.handle.net/11336/276370
identifier_str_mv Camarena, Vladimir; Williams, Monique M.; Morales, Alejo A.; Zafeer, Mohammad F.; Kilic, Okan V.; et al.; ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia; American Society for Clinical Investigation; JCI Insight; 2-2024; 1-20
2379-3708
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://insight.jci.org/articles/view/174417
info:eu-repo/semantics/altIdentifier/doi/10.1172/jci.insight.174417
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1852335763305267200
score 12.952241

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