Genes & Genomics

, Volume 38, Issue 9, pp 879–889 | Cite as

Analysis of CCM1 expression uncovers novel minor-form exons and variable splicing patterns

  • Rufino Mondejar
  • Mercedes Delgado
  • Francisca Solano
  • Guillermo Izquierdo
  • Amalia Martinez-Mir
  • Miguel LucasEmail author
Research Article


Cerebral cavernous malformations (CCM) are vascular lesions, which occur sporadically or following an autosomal dominant inheritance pattern with variable expression and incomplete penetrance. Three genes have been associated with the disease (CCM1, CCM2 and CCM3). CCM1 has been reported to express atypical transcripts in addition to alternative splicing of non-coding exons. Here, we report the identification of novel alternative splicing events in the CCM1 gene. 5′RACE analysis revealed several transcription start sites, novel exons located in introns 2 and 7, and a larger exon 13. The 5′UTR CCM1 region showed at least eight splicing variants which were differentially transcribed. The results shown here expand our knowledge of CCM1 gene expression, which seems to be more complex than previously reported. The novel minor-form exons herein described should be considered in molecular diagnosis of CCM. These findings support new functional transcript sequences that could be considered in the pathogenesis and variable clinical penetrance of Krit1-linked CCMs.


Cerebral cavernous malformations (CCMs) CCMAtypical splicing 5′UTR exons Transcription start site (TSS) Minor-form exons 



This work has been supported by grants CP10/00526 (Instituto de Salud Carlos III, Spain) and P07-CVI-02790 (Junta de Andalucía, Spain). RM received a grant for Rio Hortega specialised healthcare post-training contract (Instituto de Salud Carlos III). MD received a fellowship of Asociación Neuroinvest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This research adhered to the tenets of the Declaration of Helsinki. A written consent was obtained from each of the adult individuals tested. This study was approved by the ‘‘Committee of Ethics and Clinical Investigation’’ from Hospital Universitario Virgen Macarena.

Supplementary material

13258_2016_435_MOESM1_ESM.docx (11 kb)
CCM patients included in this study
13258_2016_435_MOESM2_ESM.tif (963 kb)
5′RACE methodology
13258_2016_435_MOESM3_ESM.docx (13 kb)
Primers used for RT-qPCR
13258_2016_435_MOESM4_ESM.docx (12 kb)
Efficiency of quantitative amplification
13258_2016_435_MOESM5_ESM.docx (11 kb)
Location of transcriptional start sites of the CCM1 gene
13258_2016_435_MOESM6_ESM.tif (556 kb)
Amplification of exon 13L with upstream exons


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Copyright information

© The Genetics Society of Korea and Springer-Science and Media 2016

Authors and Affiliations

  • Rufino Mondejar
    • 1
    • 2
  • Mercedes Delgado
    • 1
  • Francisca Solano
    • 1
  • Guillermo Izquierdo
    • 3
  • Amalia Martinez-Mir
    • 4
  • Miguel Lucas
    • 1
    Email author
  1. 1.Servicio de Biología Molecular, Facultad de MedicinaHospital Universitario Virgen MacarenaSevilleSpain
  2. 2.Laboratorio de Genómica del CáncerIDIVAL, Instituto de Investigación Marqués de ValdecillaSantanderSpain
  3. 3.Servicio de Neurología, Facultad de MedicinaHospital Universitario Virgen MacarenaSevilleSpain
  4. 4.Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSevilleSpain

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