Cargando…
Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity
LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one fu...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452625/ https://www.ncbi.nlm.nih.gov/pubmed/34545091 http://dx.doi.org/10.1038/s41467-021-25844-5 |
_version_ | 1784570110463180800 |
---|---|
author | Haro, Endika Petit, Florence Pira, Charmaine U. Spady, Conor D. Lucas-Toca, Sara Yorozuya, Lauren I. Gray, Austin L. Escande, Fabienne Jourdain, Anne-Sophie Nguyen, Andy Fellmann, Florence Good, Jean-Marc Francannet, Christine Manouvrier-Hanu, Sylvie Ros, Marian A. Oberg, Kerby C. |
author_facet | Haro, Endika Petit, Florence Pira, Charmaine U. Spady, Conor D. Lucas-Toca, Sara Yorozuya, Lauren I. Gray, Austin L. Escande, Fabienne Jourdain, Anne-Sophie Nguyen, Andy Fellmann, Florence Good, Jean-Marc Francannet, Christine Manouvrier-Hanu, Sylvie Ros, Marian A. Oberg, Kerby C. |
author_sort | Haro, Endika |
collection | PubMed |
description | LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis. |
format | Online Article Text |
id | pubmed-8452625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84526252021-10-05 Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity Haro, Endika Petit, Florence Pira, Charmaine U. Spady, Conor D. Lucas-Toca, Sara Yorozuya, Lauren I. Gray, Austin L. Escande, Fabienne Jourdain, Anne-Sophie Nguyen, Andy Fellmann, Florence Good, Jean-Marc Francannet, Christine Manouvrier-Hanu, Sylvie Ros, Marian A. Oberg, Kerby C. Nat Commun Article LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis. Nature Publishing Group UK 2021-09-20 /pmc/articles/PMC8452625/ /pubmed/34545091 http://dx.doi.org/10.1038/s41467-021-25844-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Haro, Endika Petit, Florence Pira, Charmaine U. Spady, Conor D. Lucas-Toca, Sara Yorozuya, Lauren I. Gray, Austin L. Escande, Fabienne Jourdain, Anne-Sophie Nguyen, Andy Fellmann, Florence Good, Jean-Marc Francannet, Christine Manouvrier-Hanu, Sylvie Ros, Marian A. Oberg, Kerby C. Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity |
title | Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity |
title_full | Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity |
title_fullStr | Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity |
title_full_unstemmed | Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity |
title_short | Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity |
title_sort | identification of limb-specific lmx1b auto-regulatory modules with nail-patella syndrome pathogenicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452625/ https://www.ncbi.nlm.nih.gov/pubmed/34545091 http://dx.doi.org/10.1038/s41467-021-25844-5 |
work_keys_str_mv | AT haroendika identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT petitflorence identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT piracharmaineu identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT spadyconord identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT lucastocasara identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT yorozuyalaureni identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT grayaustinl identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT escandefabienne identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT jourdainannesophie identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT nguyenandy identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT fellmannflorence identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT goodjeanmarc identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT francannetchristine identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT manouvrierhanusylvie identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT rosmariana identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity AT obergkerbyc identificationoflimbspecificlmx1bautoregulatorymoduleswithnailpatellasyndromepathogenicity |