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Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a...

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Autores principales: Gustafson, Margaret A., McCormick, Elizabeth M., Perera, Lalith, Longley, Matthew J., Bai, Renkui, Kong, Jianping, Dulik, Matthew, Shen, Lishuang, Goldstein, Amy C., McCormack, Shana E., Laskin, Benjamin L., Leroy, Bart P., Ortiz-Gonzalez, Xilma R., Ellington, Meredith G., Copeland, William C., Falk, Marni J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719858/
https://www.ncbi.nlm.nih.gov/pubmed/31479473
http://dx.doi.org/10.1371/journal.pone.0221829
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author Gustafson, Margaret A.
McCormick, Elizabeth M.
Perera, Lalith
Longley, Matthew J.
Bai, Renkui
Kong, Jianping
Dulik, Matthew
Shen, Lishuang
Goldstein, Amy C.
McCormack, Shana E.
Laskin, Benjamin L.
Leroy, Bart P.
Ortiz-Gonzalez, Xilma R.
Ellington, Meredith G.
Copeland, William C.
Falk, Marni J.
author_facet Gustafson, Margaret A.
McCormick, Elizabeth M.
Perera, Lalith
Longley, Matthew J.
Bai, Renkui
Kong, Jianping
Dulik, Matthew
Shen, Lishuang
Goldstein, Amy C.
McCormack, Shana E.
Laskin, Benjamin L.
Leroy, Bart P.
Ortiz-Gonzalez, Xilma R.
Ellington, Meredith G.
Copeland, William C.
Falk, Marni J.
author_sort Gustafson, Margaret A.
collection PubMed
description Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband’s fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.
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spelling pubmed-67198582019-09-16 Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes Gustafson, Margaret A. McCormick, Elizabeth M. Perera, Lalith Longley, Matthew J. Bai, Renkui Kong, Jianping Dulik, Matthew Shen, Lishuang Goldstein, Amy C. McCormack, Shana E. Laskin, Benjamin L. Leroy, Bart P. Ortiz-Gonzalez, Xilma R. Ellington, Meredith G. Copeland, William C. Falk, Marni J. PLoS One Research Article Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband’s fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication. Public Library of Science 2019-09-03 /pmc/articles/PMC6719858/ /pubmed/31479473 http://dx.doi.org/10.1371/journal.pone.0221829 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Gustafson, Margaret A.
McCormick, Elizabeth M.
Perera, Lalith
Longley, Matthew J.
Bai, Renkui
Kong, Jianping
Dulik, Matthew
Shen, Lishuang
Goldstein, Amy C.
McCormack, Shana E.
Laskin, Benjamin L.
Leroy, Bart P.
Ortiz-Gonzalez, Xilma R.
Ellington, Meredith G.
Copeland, William C.
Falk, Marni J.
Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes
title Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes
title_full Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes
title_fullStr Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes
title_full_unstemmed Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes
title_short Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes
title_sort mitochondrial single-stranded dna binding protein novel de novo ssbp1 mutation in a child with single large-scale mtdna deletion (slsmd) clinically manifesting as pearson, kearns-sayre, and leigh syndromes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719858/
https://www.ncbi.nlm.nih.gov/pubmed/31479473
http://dx.doi.org/10.1371/journal.pone.0221829
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