Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with  Cornelia de Lange Syndrome

Teresa-Rodrigo, María Esperanza; Eckhold, Juliane; Puisac, Beatriz; Dalski, Andreas; Gil-Rodríguez, María Concepción; Braunholz, Diana; Baquero, Carolina; Hernández-Marcos, María; Karam, Juan C. de; Ciero, Milagros; Santos‐Simarro, Fernando; Lapunzina, Pablo; Wierzba, Jolanta; Casale, César H.; Ramos, Feliciano J.; Gillessen‐Kaesbach, Gabriele; Kaiser, Frank J.; Pié, Juan

doi:10.3390/ijms150610350

Cited by 22 publications

(28 citation statements)

References 34 publications

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“…To date 333 different heterozygous NIPBL mutations have been identified in 391 CdLS patients, 28 of whom belong to 13 families ; 278 of these mutations were compiled in an excellent recent review and subsequently 55 further novel mutations have been identified .…”

Section: The Genetic Basis Of Cdlsmentioning

confidence: 99%

“…Small intragenic alterations account for the majority ( n = 267 unique mutations) of the NIPBL mutations: missense ( n = 81), nonsense ( n = 44), splice‐site mutations ( n = 59), regulatory ( n = 2) and deletions/insertions/duplications ( n = 116) . Most of these alterations are truncating mutations, which are shown or predicted to result in a partially functioning or a non‐functional truncated protein .…”

Section: The Genetic Basis Of Cdlsmentioning

confidence: 99%

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Cornelia de Lange syndrome

et al. 2014

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Cornelia de Lange syndrome (CdLS; MIM #122470, 300590, 610759, 614701, 300882) is a rare and clinically variable disorder that affects multiple organs. It is characterized by intellectual disability (mild to severe), distinctive facial features, prenatal and postnatal growth retardation, and hirsutism. Congenital anomalies include malformations of the upper limbs, gastrointestinal malformation/rotation, pyloric stenosis, diaphragmatic hernia, heart defects and genitourinary malformations. Gastroesophageal reflux disease is present in almost all patients. In addition to classic forms, milder phenotypes have been reported. To date five genes [NIPBL (Nipped-B-like protein), SMC1A (structural maintenance of chromosomes 1A), SMC3 (structural maintenance of chromosomes 3), RAD21 (human homolog of Schizosaccharomyces pombe radiation sensitive mutant 21) and HDAC8 (histone deacetylase 8)] have been associated with CdLS and mutations of these genes comprise the underlying defect in 70% of the patients. Here, we will provide a brief review of the clinical features of CdLS, summarize the known underlying genetic defects, prenatal and postnatal diagnosis possibilities, and genetic counseling.

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Section: The Genetic Basis Of Cdlsmentioning

confidence: 99%

Section: The Genetic Basis Of Cdlsmentioning

confidence: 99%

Cornelia de Lange syndrome

et al. 2014

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“…The NIPBL gene is located at position 13.2 in the short arm of chromosome 5 (Figure 2a). Delangin protein encoded by NIPBL is an ortholog of Scc2 protein in Drosophila [1,11] and consists of 47 exons which are anticipated to construct six isoforms (Figure 3a) [20].…”

Section: Discussionmentioning

confidence: 99%

De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

et al. 2020

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Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.

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“…In general, more damaging pathological variants (nonsense, frameshift) cause a more severe phenotype than less damaging pathological variants (missense) [10]. The NIPBL gene contains 47 exons and, although several transcripts have been identified in peripheral blood leukocytes [11], the main and largest size splicing variants are isoforms A and B. Both isoforms are conserved in vertebrates and have identical aminoacids from 1 to 2683, while the C-terminal ends are different [4].…”

Section: Introductionmentioning

confidence: 99%

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

Puisac

Teresa-Rodrigo

Hernández-Marcos

et al. 2017

IJMS

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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.

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Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome

Cited by 22 publications

References 34 publications

Cornelia de Lange syndrome

Cornelia de Lange syndrome

De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

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

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