title: mRNA Quantification of NIPBL Isoforms A and B in Adult and Fetal Human Tissues, and a Potentially Pathological Variant Affecting Only Isoform A in Two Patients with Cornelia de Lange Syndrome.
abstract: Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by craniofacial dysmorphia, growth retardation, limb malformations, and intellectual disability. Approximately 60% of patients with CdLS carry a recognizable pathological variant in theNIPBLgene, of which two isoforms, A and B, have been identified, and which only differ in the C-terminal segment. In this work, we describe the distribution pattern of the isoforms A and B mRNAs in tissues of adult and fetal origin, by qPCR (quantitative polymerase chain reaction). Our results show a higher gene expression of the isoform A, even though both seem to have the same tissue distribution. Interestingly, the expression in fetal tissues is higher than that of adults, especially in brain and skeletal muscle. Curiously, the study of fibroblasts of two siblings with a mild CdLS phenotype and a pathological variant specific of the isoform A ofNIPBL(c.8387A > G; P.Tyr2796Cys), showed a similar reduction in both isoforms, and a normal sensitivity to DNA damage. Overall, these results suggest that the position of the pathological variant at the 3´ end of theNIPBLgene affecting only isoform A, is likely to be the cause of the atypical mild phenotype of the two brothers.
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. puisac@unizar.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. eteresa@unizar.es.
authors.forename: María-Esperanza
authors.initials: ME
authors.lastname: Teresa-Rodrigo
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. mhmarcos@unizar.es.
authors.forename: María
authors.initials: M
authors.lastname: Hernández-Marcos
authors.affiliation: Department of Pediatrics, Hospital Pablo Tobón Uribe, 05001000 Medellín, Colombia. carobaque@gmail.com.
authors.forename: Carolina
authors.initials: C
authors.lastname: Baquero-Montoya
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. mcgil@unizar.es.
authors.forename: María-Concepción
authors.initials: MC
authors.lastname: Gil-Rodríguez
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. Torkild.Visnes@ki.se.
authors.forename: Torkild
authors.initials: T
authors.lastname: Visnes
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. Christopher.Bot@ki.se.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bot
authors.affiliation: Molecular Modelling Group, Center of Molecular Biology "Severo Ochoa" (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain. pagomez@cbm.csic.es.
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.affiliation: Section for Functional Genetics at the Institute of Human Genetics, University of Lübeck, D-23538 Lübeck, Germany. frank.kaiser@uk-sh.de.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. framos@unizar.es.|Unit of Clinical Genetics, Department of Paediatrics, Hospital Clínico Universitario "Lozano Blesa", CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. framos@unizar.es.
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. Lena.Strom@ki.se.
authors.forename: Lena
authors.initials: L
authors.lastname: Ström
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. juanpie@unizar.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
mesh_terms: D000293:Adolescent; D001921:Brain / Q000196:embryology / Q000378:metabolism; D018797:Cell Cycle Proteins; D002648:Child; D003635:De Lange Syndrome / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger
keywords: Cornelia de Lange syndrome; NIPBL isoform A; NIPBL isoform B; NIPBL pathological variant; adult tissues; fetal tissues; mRNA; splicing variants