A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism - Sorbonne Université Access content directly
Journal Articles American Journal of Human Genetics Year : 2022

A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism

Shridhar Parthasarathy
  • Function : Author
Sarah Mckeown Ruggiero
  • Function : Author
Antoinette Gelot
  • Function : Author
Fernanda Soardi
  • Function : Author
Bethânia Ribeiro
  • Function : Author
Douglas Pires
  • Function : Author
David Ascher
  • Function : Author
Alain Schmitt
  • Function : Author
Caroline Rambaud
  • Function : Author
Alfonso Represa
  • Function : Author
Hongbo Xie
  • Function : Author
Laina Lusk
  • Function : Author
Olivia Wilmarth
  • Function : Author
Pamela Pojomovsky Mcdonnell
  • Function : Author
Olivia Juarez
  • Function : Author
Alexandra Grace
  • Function : Author
Domitille Gras
  • Function : Author
Samuel Pierce
  • Function : Author
Benjamin Kennedy
  • Function : Author
Sergio Pena
  • Function : Author
Ingo Helbig
  • Function : Author
Vishnu Anand Cuddapah
  • Function : Author

Abstract

Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied with a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in 39 pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, c.1197−8G>A (GenBank: NM_001288739.1), which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of enlarged synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.Arg399Trp and p.Gly401Asp, had a similar DEE phenotype. In contrast, one individual with a missense variant affecting exon 10b, p.Pro405Leu, which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants as well as the possibility of splice site variants acting through a dominant-negative mechanism.

Dates and versions

hal-04573492 , version 1 (13-05-2024)

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Shridhar Parthasarathy, Sarah Mckeown Ruggiero, Antoinette Gelot, Fernanda Soardi, Bethânia Ribeiro, et al.. A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism. American Journal of Human Genetics, 2022, 109 (12), pp.2253-2269. ⟨10.1016/j.ajhg.2022.11.002⟩. ⟨hal-04573492⟩
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