Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A&gt;G mtDNA variant in a large multigenerational family

Kullar, Peter; Gómez-Durán, Aurora; Gammage, Payam A.; Garone, Caterina; Minczuk, Michal; Golder, Zoe J.; Wilson, Janet A.; Montoya, Julio; Häkli, Sanna; Kärppä, Mikko; Horvath, Rita; Majamaa, Kari; Chinnery, Patrick F.

doi:10.1093/brain/awx295

Cited by 22 publications

(16 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It may be that the role of SSBP1 is more cell-type specific. 45 The variants reported herein are missense changes that affect amino acid residues in close proximity in the SSBP1 tertiary structure. 43 It is likely that biallelic loss of gene function (knockout) would be incompatible with life (http://www.…”

Section: Discussionmentioning

confidence: 94%

“…In addition, recently, it was reported that a heterozygous start loss variant in the SSBP1 cosegregated with sensorineural hearing loss in a large family harboring the variable penetrance m.1555A>G maternally inherited deafness variant. The authors stated that the SSBP1 variant leads to reduced SSBP1 level and perturbation of mtDNA metabolism, but the presence of an SSBP1 start loss mutation alone was not associated with disease unless in conjunction with the m.1555A>G variant …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

Jurkutė

Leu

Pogoda

et al. 2019

Annals of Neurology

View full text Add to dashboard Cite

Objective: Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality. Methods: Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model. Results: We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was View this article online at wileyonlinelibrary.com.Additional supporting information can be found in the online version of this article.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

Jurkutė

Leu

Pogoda

et al. 2019

Annals of Neurology

View full text Add to dashboard Cite

show abstract

“…This is explained by the sequence domain affected by the rRNA mutation, relevant for aminoglycoside interaction and resistance and possibly leading to drug bacterial/human cross‐reactivity, with depression of human mtDNA translation [33,73]. Yet, in vitro experiments strongly indicated the modifying role possibly played by the nDNA [74] and in specific pedigrees the co‐segregation and possible functional relevance of nDNA variants has been documented [75,76].…”

Section: Mitochondrial Diseases With Primary Mutations Affecting Mtdnamentioning

confidence: 99%

Mitochondrial diseases in adults

et al. 2020

View full text Add to dashboard Cite

Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype–phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy‐dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.

show abstract

“…As cellular organelles present in almost all eukaryotic cells, mitochondria are places where ATP is biosynthesized and are essential for various cellular biological processes, including reactive oxygen species (ROS) generation, intracellular Ca 2+ signaling, heme metabolism, intrinsic apoptosis, mitophagy, metabolism and cell cycle progression (Yien et al, 2014;Picard et al, 2016;van der Bliek et al, 2017;Gómez-Durán et al, 2018). Genetic mutations in mitochondrial DNA (mtDNA) and perturbations in mitochondrial proteins can cause dysfunction of mitochondria that has been shown to be tightly associated with many mitochondrial diseases and cancer (Taylor and Turnbull, 2005;Garone et al, 2012aGarone et al, ,b, 2013Gómez-Durán et al, 2012;Ronchi et al, 2012;Kullar et al, 2017;Chinnery and Gómez-Durán, 2018;Garone and Viscomi, 2018;Andreazza et al, 2019). Therefore, mitochondria are promising targets for the treatment of these diseases (Gómez-Durán et al, 2010;Zong et al, 2016;Dong et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Mitoepigenetics and Its Emerging Roles in Cancer

Dong

Cui

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

In human beings, there is a ∼16,569 bp circular mitochondrial DNA (mtDNA) encoding 22 tRNAs, 12S and 16S rRNAs, 13 polypeptides that constitute the central core of ETC/OxPhos complexes, and some non-coding RNAs. Recently, mtDNA has been shown to have some covalent modifications such as methylation or hydroxylmethylation, which play pivotal epigenetic roles in mtDNA replication and transcription. Posttranslational modifications of proteins in mitochondrial nucleoids such as mitochondrial transcription factor A (TFAM) also emerge as essential epigenetic modulations in mtDNA replication and transcription. Post-transcriptional modifications of mitochondrial RNAs (mtRNAs) including mt-rRNAs, mt-tRNAs and mt-mRNAs are important epigenetic modulations. Besides, mtDNA or nuclear DNA (n-DNA)-derived non-coding RNAs also play important roles in the regulation of translation and function of mitochondrial genes. These evidences introduce a novel concept of mitoepigenetics that refers to the study of modulations in the mitochondria that alter heritable phenotype in mitochondria itself without changing the mtDNA sequence. Since mitochondrial dysfunction contributes to carcinogenesis and tumor development, mitoepigenetics is also essential for cancer. Understanding the mode of actions of mitoepigenetics in cancers may shade light on the clinical diagnosis and prevention of these diseases. In this review, we summarize the present study about modifications in mtDNA, mtRNA and nucleoids and modulations of mtDNA/nDNA-derived non-coding RNAs that affect mtDNA translation/function, and overview recent studies of mitoepigenetic alterations in cancer.

show abstract

Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family

Cited by 22 publications

References 24 publications

SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

Mitochondrial diseases in adults

Mitoepigenetics and Its Emerging Roles in Cancer

Contact Info

Product

Resources

About