Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C)
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the <i>DNM1L</i> gene, required for mitochondrial fragmentation. <i>DNM1L</i> dominant pathogenic variants lead to progressive neurological disorders with early exitus. Herein w...
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doaj-d33a4106e2954927801c2b1cbe40f41a2021-09-26T00:12:43ZengMDPI AGGenes2073-44252021-08-01121295129510.3390/genes12091295Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C)Claudia Piccoli0Rosella Scrima1Annamaria D’Aprile2Massimiliano Chetta3Olga Cela4Consiglia Pacelli5Maria Ripoli6Giovanna D’Andrea7Maurizio Margaglione8Nenad Bukvic9Nazzareno Capitanio10Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyDepartment of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyCytogenetic Unit, Azienda Ospedaliera Universitaria, Ospedali Riuniti, 71121 Foggia, ItalyU.O.C. Genetica Medica e di Laboratorio, Ospedale Antonio Cardarelli, 80131 Napoli, ItalyDepartment of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyDepartment of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyProduction Unit of Advanced Therapies (UPTA), Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), I.R.C.C.S. Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, FG, ItalyDepartment of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyDepartment of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyMedical Genetic Unit, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, 70124 Bari, ItalyDepartment of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, ItalyMitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the <i>DNM1L</i> gene, required for mitochondrial fragmentation. <i>DNM1L</i> dominant pathogenic variants lead to progressive neurological disorders with early exitus. Herein we report on the case of a boy affected by epileptic encephalopathy carrying two heterozygous variants (<i>in cis</i>) of the <i>DNM1L</i> gene: a pathogenic variant (PV) c.1085G>A (p.Gly362Asp) accompanied with a variant of unknown significance (VUS) c.1535T>C (p.Ile512Thr). Amplicon sequencing of the mother’s DNA revealed the presence of the PV and VUS in 5% of cells, with the remaining cells presenting only VUS. Functional investigations performed on the patient and his mother’s cells unveiled altered mitochondrial respiratory chain activities, network architecture and Ca<sup>2+</sup> homeostasis as compared with healthy unrelated subjects’ samples. Modelling Drp1 harbouring the two variants, separately or in combination, resulted in structural changes as compared with Wt protein. Considering the clinical history of the mother, PV transmission by a maternal germline mosaicism mechanism is proposed. Altered Drp1 function leads to changes in the mitochondrial structure and bioenergetics as well as in Ca<sup>2+</sup> homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.https://www.mdpi.com/2073-4425/12/9/1295DNM1LDrp1mitochondrial fissionencephalopathygenetic mosaicism |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Claudia Piccoli Rosella Scrima Annamaria D’Aprile Massimiliano Chetta Olga Cela Consiglia Pacelli Maria Ripoli Giovanna D’Andrea Maurizio Margaglione Nenad Bukvic Nazzareno Capitanio |
spellingShingle |
Claudia Piccoli Rosella Scrima Annamaria D’Aprile Massimiliano Chetta Olga Cela Consiglia Pacelli Maria Ripoli Giovanna D’Andrea Maurizio Margaglione Nenad Bukvic Nazzareno Capitanio Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C) Genes DNM1L Drp1 mitochondrial fission encephalopathy genetic mosaicism |
author_facet |
Claudia Piccoli Rosella Scrima Annamaria D’Aprile Massimiliano Chetta Olga Cela Consiglia Pacelli Maria Ripoli Giovanna D’Andrea Maurizio Margaglione Nenad Bukvic Nazzareno Capitanio |
author_sort |
Claudia Piccoli |
title |
Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C) |
title_short |
Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C) |
title_full |
Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C) |
title_fullStr |
Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C) |
title_full_unstemmed |
Pathogenic <i>DNM1L</i> Variant (1085G>A) Linked to Infantile Progressive Neurological Disorder: Evidence of Maternal Transmission by Germline Mosaicism and Influence of a Contemporary in cis Variant (1535T>C) |
title_sort |
pathogenic <i>dnm1l</i> variant (1085g>a) linked to infantile progressive neurological disorder: evidence of maternal transmission by germline mosaicism and influence of a contemporary in cis variant (1535t>c) |
publisher |
MDPI AG |
series |
Genes |
issn |
2073-4425 |
publishDate |
2021-08-01 |
description |
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the <i>DNM1L</i> gene, required for mitochondrial fragmentation. <i>DNM1L</i> dominant pathogenic variants lead to progressive neurological disorders with early exitus. Herein we report on the case of a boy affected by epileptic encephalopathy carrying two heterozygous variants (<i>in cis</i>) of the <i>DNM1L</i> gene: a pathogenic variant (PV) c.1085G>A (p.Gly362Asp) accompanied with a variant of unknown significance (VUS) c.1535T>C (p.Ile512Thr). Amplicon sequencing of the mother’s DNA revealed the presence of the PV and VUS in 5% of cells, with the remaining cells presenting only VUS. Functional investigations performed on the patient and his mother’s cells unveiled altered mitochondrial respiratory chain activities, network architecture and Ca<sup>2+</sup> homeostasis as compared with healthy unrelated subjects’ samples. Modelling Drp1 harbouring the two variants, separately or in combination, resulted in structural changes as compared with Wt protein. Considering the clinical history of the mother, PV transmission by a maternal germline mosaicism mechanism is proposed. Altered Drp1 function leads to changes in the mitochondrial structure and bioenergetics as well as in Ca<sup>2+</sup> homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV. |
topic |
DNM1L Drp1 mitochondrial fission encephalopathy genetic mosaicism |
url |
https://www.mdpi.com/2073-4425/12/9/1295 |
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