A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism - Sorbonne Université
Article Dans Une Revue American Journal of Human Genetics Année : 2022

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

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

Résumé

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 et 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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