Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2024

Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria

Résumé

Pathogenic variants in the MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the CNS. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole genome analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in the MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline-rich domain and the transmembrane domain 1 (TM1). MFN2 is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial fusion, shaping large mitochondrial networks within cells. In silico modelling showed that the loss of the TM1 domain resulted in a drastically altered topological insertion of the protein in the mitochondrial outer membrane. Fetus fibroblasts, investigated by fluorescent cell imaging, electron microscopy and time-lapse recording, showed a sharp alteration of the mitochondrial network, with clumped mitochondria and clusters of tethered mitochondria unable to fuse. Multiple deficiencies of respiratory chain complexes with severe impairment of complex I were also evidenced in patient fibroblasts, without involvement of mitochondrial DNA instability. This is the first reported case of a severe developmental defect due to MFN2 deficiency with clumped mitochondria.
Fichier sous embargo
Fichier sous embargo
Date de visibilité indéterminée

Dates et versions

inserm-04410829 , version 1 (22-01-2024)

Identifiants

Citer

Arnaud Chevrollier, Adeline Alice Bonnard, Lyse Ruaud, Naïg Gueguen, Laurence Perrin, et al.. Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria. Brain - A Journal of Neurology , 2024, 147 (1), pp.91 - 99. ⟨10.1093/brain/awad347⟩. ⟨inserm-04410829⟩
18 Consultations
2 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More