Pathogenic DNM1L 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 DNM1L gene, required for mitochondrial fragmentation. DNM1L dominant pathogenic variants lead to progressive neurological disorders with early exitus. Herein we report on the case of a boy affected...

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Published inGenes Vol. 12; no. 9; p. 1295
Main Authors Piccoli, Claudia, Scrima, Rosella, D’Aprile, Annamaria, Chetta, Massimiliano, Cela, Olga, Pacelli, Consiglia, Ripoli, Maria, D’Andrea, Giovanna, Margaglione, Maurizio, Bukvic, Nenad, Capitanio, Nazzareno
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 24.08.2021
MDPI
Subjects
Adult
Alleles
Bioenergetics
boys
calcium
Calcium - metabolism
Calcium homeostasis
Case Report
Cells, Cultured
Child
Cytochrome
DNA
DNA sequencing
Dynamins - chemistry
Dynamins - genetics
Dynamins - metabolism
Electron transport
electron transport chain
Encephalopathy
Epilepsy
Female
Fibroblasts
Genes
germ cells
Germ-Line Mutation
heterozygosity
Heterozygote
Homeostasis
Humans
Infant
Male
Maternal Inheritance
Mitochondria
Mitochondrial Diseases - genetics
Mitochondrial Diseases - metabolism
Mitochondrial Diseases - pathology
Mitochondrial DNA
Mitochondrial Dynamics
Mosaicism
Mutation, Missense
Neurological diseases
Organelles
patients
phenotype
Phenotypes
Polymerase chain reaction
Protein Conformation
Software
Spasms, Infantile - genetics
Spasms, Infantile - metabolism
Spasms, Infantile - pathology
genetic mosaicism
DNM1L
mitochondrial fission
encephalopathy
Drp1
Online AccessGet full text
ISSN2073-4425
2073-4425
DOI10.3390/genes12091295

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Abstract Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation. DNM1L 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 (in cis) of the DNM1L 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 Ca2+ 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 Ca2+ homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
AbstractList Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation. DNM1L 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 (in cis) of the DNM1L 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 Ca2+ 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 Ca2+ homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation. DNM1L 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 (in cis) of the DNM1L 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 Ca2+ 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 Ca2+ homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the gene, required for mitochondrial fragmentation. 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 ( ) of the 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 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 homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation. DNM1L 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 (in cis) of the DNM1L 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 Ca2+ 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 Ca2+ homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation. DNM1L 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 ( in cis ) of the DNM1L 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 2+ 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 2+ homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation. DNM1L 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 (in cis) of the DNM1L 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 Ca²⁺ 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 Ca²⁺ homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
Author Chetta, Massimiliano
Piccoli, Claudia
Ripoli, Maria
Cela, Olga
Scrima, Rosella
Pacelli, Consiglia
Margaglione, Maurizio
Bukvic, Nenad
Capitanio, Nazzareno
D’Andrea, Giovanna
D’Aprile, Annamaria
AuthorAffiliation 3 U.O.C. Genetica Medica e di Laboratorio, Ospedale Antonio Cardarelli, 80131 Napoli, Italy; m_ax@libero.it
5 Medical Genetic Unit, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, 70124 Bari, Italy
4 Production 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, Italy; m.ripoli@operapadrepio.it
2 Cytogenetic Unit, Azienda Ospedaliera Universitaria, Ospedali Riuniti, 71121 Foggia, Italy; annamariadaprile@libero.it
1 Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy; claudia.piccoli@unifg.it (C.P.); rosella.scrima@unifg.it (R.S.); olga.cela@unifg.it (O.C.); consiglia.pacelli@unifg.it (C.P.); giovanna.dandrea@unifg.it (G.D.); maurizio.margaglione@unifg.it (M.M.)
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– name: 1 Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy; claudia.piccoli@unifg.it (C.P.); rosella.scrima@unifg.it (R.S.); olga.cela@unifg.it (O.C.); consiglia.pacelli@unifg.it (C.P.); giovanna.dandrea@unifg.it (G.D.); maurizio.margaglione@unifg.it (M.M.)
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Keywords genetic mosaicism
DNM1L
mitochondrial fission
encephalopathy
Drp1
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Snippet Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation....
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the gene, required for mitochondrial fragmentation. dominant...
Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the DNM1L gene, required for mitochondrial fragmentation....
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StartPage 1295
SubjectTerms Adult
Alleles
Bioenergetics
boys
calcium
Calcium - metabolism
Calcium homeostasis
Case Report
Cells, Cultured
Child
Cytochrome
DNA
DNA sequencing
Dynamins - chemistry
Dynamins - genetics
Dynamins - metabolism
Electron transport
electron transport chain
Encephalopathy
Epilepsy
Female
Fibroblasts
Genes
germ cells
Germ-Line Mutation
heterozygosity
Heterozygote
Homeostasis
Humans
Infant
Male
Maternal Inheritance
Mitochondria
Mitochondrial Diseases - genetics
Mitochondrial Diseases - metabolism
Mitochondrial Diseases - pathology
Mitochondrial DNA
Mitochondrial Dynamics
Mosaicism
Mutation, Missense
Neurological diseases
Organelles
patients
phenotype
Phenotypes
Polymerase chain reaction
Protein Conformation
Software
Spasms, Infantile - genetics
Spasms, Infantile - metabolism
Spasms, Infantile - pathology
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Title Pathogenic DNM1L 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)
URI https://www.ncbi.nlm.nih.gov/pubmed/34573276
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Volume 12
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