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Int J Mol Sci. 2017 Feb 23;18(3). pii: E481. doi: 10.3390/ijms18030481.

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.

Author information

1
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.
2
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.
3
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.
4
Department of Pediatrics, Hospital Pablo Tobón Uribe, 05001000 Medellín, Colombia. carobaque@gmail.com.
5
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.
6
Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. Torkild.Visnes@ki.se.
7
Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. Christopher.Bot@ki.se.
8
Molecular Modelling Group, Center of Molecular Biology "Severo Ochoa" (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain. pagomez@cbm.csic.es.
9
Section for Functional Genetics at the Institute of Human Genetics, University of Lübeck, D-23538 Lübeck, Germany. frank.kaiser@uk-sh.de.
10
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.
11
Unit of Clinical Genetics, Department of Paediatrics, Hospital Clínico Universitario "Lozano Blesa", CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain. framos@unizar.es.
12
Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. Lena.Strom@ki.se.
13
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.

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 the NIPBL gene, 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 of NIPBL (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 the NIPBL gene affecting only isoform A, is likely to be the cause of the atypical mild phenotype of the two brothers.

KEYWORDS:

Cornelia de Lange syndrome; NIPBL isoform A; NIPBL isoform B; NIPBL pathological variant; adult tissues; fetal tissues; mRNA; splicing variants

PMID:
28241484
PMCID:
PMC5372497
DOI:
10.3390/ijms18030481
[Indexed for MEDLINE]
Free PMC Article

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