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Esposito, A.* ; Falace, A.* ; Wagner, M. ; Gal, M.* ; Mei, D.* ; Conti, V.* ; Pisano, T.* ; Aprile, D.* ; Cerullo, M.S.* ; De Fusco, A.* ; Giovedì, S.* ; Seibt, A.* ; Magen, D.* ; Polster, T.* ; Eran, A.* ; Stenton, S. ; Fiorillo, C.* ; Ravid, S.* ; Mayatepek, E.* ; Hafner, H.* ; Wortmann, S.B. ; Levanon, E.Y.* ; Marini, C.* ; Mandel, H.* ; Benfenati, F.* ; Distelmaier, F.* ; Fassio, A.* ; Guerrini, R.*

Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.

Brain 142, 3876-3891 (2019)
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Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C4T (p.Ala1712Val) missense substitution and the c.4478C4G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C4A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G4A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients’ fibroblasts also exhibited an increased LysoTrackerÕ signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autophagy ; Developmental And Epileptic Encephalopathy ; Neuropathy ; Ohtahara Syndrome ; Progressive Disorder; Gdp/gtp Exchange Protein; Neuronal Migration; Synaptic Vesicles; Vici Syndrome; Rabconnectin-3; Annotations; Disorders; Variants; Binds; Pump
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Quellenangaben Volume: 142, Issue: 12, Pages: 3876-3891 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed