Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes

Shamseldin, Hanan E.; Alshammari, Muneera; Al‐Sheddi, Tarfa; Salih, Mustafa A.; Alkhalidi, Hisham; Kentab, Amal Y.; Repetto, Gabriela M.; Hashem, Mais; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2012-100836

Cited by 162 publications

(139 citation statements)

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“…A truncating mutation in MFF was first identified in a Saudi Arabian boy with delayed psychomotor development, spasticity, optic atrophy, and bilateral, increased signal intensities of the basal ganglia (190). Furthermore, recently three boys with similar overlapping phenotype were found to carry truncating mutations in MFF (191).…”

Section: Atpase Family Aaa-domain Containing Protein 3a (Atad3a)supporting

confidence: 81%

“…MFF is anchored in the OMM through its C-terminal transmembrane segment. The sequence of MFF indicates that it also interacts with other proteins and participate in protein complexes that mediate the fission pathway (33,34).A truncating mutation in MFF was first identified in a Saudi Arabian boy with delayed psychomotor development, spasticity, optic atrophy, and bilateral, increased signal intensities of the basal ganglia (190). Furthermore, recently three boys with similar overlapping phenotype were found to carry truncating mutations in MFF (191).…”

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confidence: 99%

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Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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Section: Atpase Family Aaa-domain Containing Protein 3a (Atad3a)supporting

confidence: 81%

mentioning

confidence: 99%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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“…Furthermore, the success we have had in combining autozygome and exome analysis in delineating the genetic architecture of other genetically heterogeneous disorders, for example, Osteogenesis imperfecta, retinal dystrophy, cataract, mitochondrial diseases, Bardet-Biedl syndrome, and Joubert syndrome 26,[28][29][30][31] 33 ), encouraged us to use a similar approach on MKS to not only determine the mutation distribution in known MKS disease genes but to also potentially identify novel candidate disease genes.…”

Section: Discussionmentioning

confidence: 99%

“…28,29,34 In order to explore the potential of revealing novel disease genes, all cases in which autozygome-guided mutational analysis was negative were exome sequenced. As we have shown previously, autozygome served as an extremely powerful filter of the resulting variants.…”

Section: Head and Neckmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

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“…On the contrary, so far five disease-causing mutations have been identified within FARS2 gene encoding HmtPheRS (Figure 4 and Table 4). [122][123][124][125] FARS2 gene is located in chromosome 6; containing 7 exons, of which 2-7 are protein coding. 122 The effects of the disease-associated mutations on aminoacylation activity and enzyme stability have been analyzed in HmtPheRS.…”

Section: Phers In Pathophysiology Human Disorders Associated With Phementioning

confidence: 99%

Phenylalanyl-tRNA synthetase

Chakraborty¹,

Banerjee²

2016

RRBC

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Phenylalalnyl-tRNA synthetase (PheRS), a member of class II aminoacyl-tRNA synthetases, catalyzes the synthesis of phenylalanyl-tRNA Phe (Phe-tRNA Phe ). Hence, like other aminoacyl-tRNA synthetases, PheRS also plays a crucial role in the cellular translation process. Structural characterization demonstrates remarkable architectural diversity ranging from monomer to hetero-oligomer. Heterotetrameric PheRS contains an editing domain to proofread misincorporation of non-cognate amino acids. However, editing activity is absent in monomeric PheRS. PheRS has also shown some noncanonical functions, such as DNA binding properties, suggesting its involvement in complex regulatory pathways. Engineered mutants with relaxed substrate specificities of PheRS can be a promising tool for chemical and synthetic biology. Because of substantial structural variations among species due to evolutionary divergence, PheRS may be validated as a novel drug target. Human PheRS gene mutations have recently been implicated in several neurological disorders prompting structure-function studies to elucidate the molecular role of PheRS in such pathologies. In this review on PheRS, we will briefly cover all of the aforementioned aspects and our current understanding about the enzyme.

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Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes

Abstract: These findings expand the repertoire of genes that are mutated in patients with mitochondrial disorders and highlight the value of integrating genomic approaches in the evaluation of these patients.

Cited by 162 publications

References 33 publications

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

Phenylalanyl-tRNA synthetase

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