Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

Endika Haro, Florence Petit, Charmaine U. Pira, Conor D. Spady, Sara Lucas-Toca, Lauren I. Yorozuya, Austin L. Gray, Fabienne Escande, Anne-Sophie Jourdain, Andy Nguyen, Florence Fellmann, Jean-Marc Good, Christine Francannet, Sylvie Manouvrier-Hanu, Marian A. Ros () and Kerby C. Oberg ()
Additional contact information
Endika Haro: Loma Linda University School of Medicine
Florence Petit: Clinique de Génétique, CHU Lille
Charmaine U. Pira: Loma Linda University School of Medicine
Conor D. Spady: Loma Linda University School of Medicine
Sara Lucas-Toca: Instituto de Biomedicina y Biotecnología de Cantabria, CSIC–SODERCAN-Universidad de Cantabria
Lauren I. Yorozuya: Loma Linda University School of Medicine
Austin L. Gray: Loma Linda University School of Medicine
Fabienne Escande: EA7364 RADEME, Université de Lille
Anne-Sophie Jourdain: EA7364 RADEME, Université de Lille
Andy Nguyen: Loma Linda University School of Medicine
Florence Fellmann: Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois
Jean-Marc Good: Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois
Christine Francannet: Service de génétique médicale, CHU Estaing
Sylvie Manouvrier-Hanu: Clinique de Génétique, CHU Lille
Marian A. Ros: Instituto de Biomedicina y Biotecnología de Cantabria, CSIC–SODERCAN-Universidad de Cantabria
Kerby C. Oberg: Loma Linda University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25844-5

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