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Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation

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Abstract

Cerebral cavernous malformation (CCM) is a vascular disease that affects the central nervous system, which familial form is due to autosomal dominant mutations in the genes KRIT1(CCM1), MGC4607(CCM2), and PDCD10(CCM3). Patients affected by the PDCD10 mutations usually have the onset of symptoms at an early age and a more aggressive phenotype. The aim of this study is to investigate the molecular mechanism involved with CCM3 disease pathogenesis. Herein, we report two typical cases of CCM3 phenotype and compare the clinical and neuroradiological findings with five patients with a familial form of KRIT1 or CCM2 mutations and six patients with a sporadic form. In addition, we evaluated the PDCD10 gene expression by qPCR and developed a bioinformatic pipeline to understand the structural changes of mutations. The two CCM3 patients had an early onset of symptoms and a high lesion burden. Furthermore, the sequencing showed that Patient 1 had a frameshift mutation in c.222delT; p.(Asn75Thrfs*14) that leads to lacking the last 124 C-terminal amino acids on its primary structure and Patient 2 had a variant on the splicing site region c.475-2A > G. The mRNA expression was fourfold lower in both patients with PDCD10 mutation. Using in silico analysis, we identify that the frameshift mutation transcript lacks the C-terminal FAT-homology domain compared to the wild-type PDCD10 and preserves the N-terminal dimerization domain. The two patients studied here allow estimating the potential impact of mutations in clinical interpretation as well as support to better understand the mechanism and pathogenesis of CCM3.

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Acknowledgements

The authors thank the Cavernoma Alliance Brazil Research Institute – Aliança Cavernoma Brasil for the logistic assistance.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Brazilian National Council for Scientific and Technological Development (CNPq Number 440779/2016-2), Senator Romario Faria parliamentary amendment (no. 37990007 EIND), financial support of Coordination for the Improvement of Higher Education Personnel (CAPES Number 88887.130752/2016-00), FAPERJ E-26/210.657/2021, E-26/210.273/2018 and E-26/201.040/2021 and Chamada Pública MCTI/FINEP/CT-INFRA-PROINFRA 02/2014 – Equipamentos Multiusuários – Ref. nº 0097/2016.

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Authors and Affiliations

  1. Programa de Pós-Graduação Em Neurologia, Laboratório de Neurociências Translacional, Universidade Federal Do Estado Do Rio de Janeiro, Rio de Janeiro RJ, Brazil

    Gustavo da Fontoura Galvão, Elielson Veloso da Silva, Luisa Menezes Trefilio, Soniza Vieira Alves-Leon, Fabrícia Lima Fontes-Dantas & Jorge Marcondes de Souza

  2. Departamento de Neurocirurgia, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro RJ, Brazil

    Gustavo da Fontoura Galvão & Jorge Marcondes de Souza

  3. Programa de Pós-Graduação Em Neurologia E Neurociências, Universidade Federal Fluminense, Rio de Janeiro RJ, Brazil

    Elielson Veloso da Silva

  4. Departamento de Neurologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro RJ, Brazil

    Soniza Vieira Alves-Leon

  5. Departamento de Farmacologia E Psicobiologia, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual Do Rio de Janeiro, Rio de Janeiro RJ, Brazil

    Fabrícia Lima Fontes-Dantas

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Contributions

Material preparation and analysis were performed by Gustavo da Fontoura Galvão and Fabrícia Lima Fontes-Dantas. Data collection was performed by Gustavo da Fontoura Galvão and Jorge Marcondes de Souza. Sample processing and lab work was performed by Fabrícia Lima Fontes-Dantas, Elielson Veloso da Silva, and Luisa Menezes Trefilio. The first draft of the manuscript was written by Gustavo da Fontoura Galvão and review by Fabrícia Lima Fontes-Dantas and Jorge Marcondes de Souza. Funding acquisition, resources, and supervision were performed by Soniza Vieira Alves-Leon, Jorge Marcondes de Souza, and Fabrícia Lima Fontes-Dantas. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Fabrícia Lima Fontes-Dantas or Jorge Marcondes de Souza.

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da Fontoura Galvão, G., da Silva, E.V., Trefilio, L.M. et al. Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation. Transl. Stroke Res. 15, 411–421 (2024). https://doi.org/10.1007/s12975-023-01131-x

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