Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

Bayat, Vafa; Thiffault, Isabelle; Jaiswal, Manish; Tétreault, Martine; Donti, Taraka; Sasarman, Florin; Bernard, Geneviève; Demers-Lamarche, Julie; Dicaire, Marie‐Josée; Mathieu, Jean-Pierre; Vanasse, Michel; Bouchard, Jean‐Pierre; Rioux, Marie-France; Lourenço, Charles Marques; Li, Zhihong; Haueter, Claire; Shoubridge, Eric A.; Graham, Brett H.; Brais, Bernard; Bellen, Hugo J.

doi:10.1371/journal.pbio.1001288

Cited by 149 publications

(144 citation statements)

References 94 publications

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“…Specifically, these retrogenes were able to completely rescue the phenotype of knockout mutants for 1:1 orthologs of their parental genes in Drosophila (MARS2 [Bayat et al 2012] and RNF113A [Carney et al 2013]) or perform the same enzymatic process as the endogenous copy in yeast (TRMT12) (Rodriguez et al 2012). These studies support a substantial functional overlap between orphan and parent, suggesting that new retrogenes can evolve to carry out fundamental and ancient cellular functions.…”

Section: Orphan Retrogenes Functionally Replace Their Parentsmentioning

confidence: 67%

“…We show that orphan retrogenes recapitulate the expression of their respective parental genes remarkably well, indicating that they functionally replace the parent. Experimental rescue of the parental gene in outgroup model species, using human orphan retrogenes (Bayat et al 2012;Rodriguez et al 2012;Carney et al 2013), further supports the functional equivalency between orphan retrogenes and their lost parental genes. Orphan retrogenes therefore constitute a unique system to study fundamental processes characterizing new gene evolution.…”

Section: Wwwgenomeorgmentioning

confidence: 73%

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The life history of retrocopies illuminates the evolution of new mammalian genes

et al. 2016

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New genes contribute substantially to adaptive evolutionary innovation, but the functional evolution of new mammalian genes has been little explored at a broad scale. Previous work established mRNA-derived gene duplicates, known as retrocopies, as models for the study of new gene origination. Here we combine mammalian transcriptomic and epigenomic data to unveil the processes underlying the evolution of stripped-down retrocopies into complex new genes. We show that although some robustly expressed retrocopies are transcribed from preexisting promoters, most evolved new promoters from scratch or recruited proto-promoters in their genomic vicinity. In particular, many retrocopy promoters emerged from ancestral enhancers (or bivalent regulatory elements) or are located in CpG islands not associated with other genes. We detected 88–280 selectively preserved retrocopies per mammalian species, illustrating that these mechanisms facilitated the birth of many functional retrogenes during mammalian evolution. The regulatory evolution of originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated co-option of distant promoters and allowed expression of alternative isoforms. While young retrogenes are often initially expressed in the testis, increased regulatory and structural complexities allowed retrogenes to functionally diversify and evolve somatic organ functions, sometimes as complex as those of their parents. Thus, some retrogenes evolved the capacity to temporarily substitute for their parents during the process of male meiotic X inactivation, while others rendered parental functions superfluous, allowing for parental gene loss. Overall, our reconstruction of the “life history” of mammalian retrogenes highlights retroposition as a general model for understanding new gene birth and functional evolution.

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Section: Orphan Retrogenes Functionally Replace Their Parentsmentioning

confidence: 67%

Section: Wwwgenomeorgmentioning

confidence: 73%

The life history of retrocopies illuminates the evolution of new mammalian genes

et al. 2016

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“…These are the areas with higher expression of spastacsin in the brain and this pattern helps us to understand why movement disorders are so frequent in SPG 11 42 . Despite this, one must consider that thinning of the corpus callosum is not SPG11-specific, because it is also found in other HSPs such as: SPG 4,7,15,18,21,46,47,49 and 54 3,11,21,44,45,46 . Progressive hydrocephalus due to aqueductal stenosis is highly suggestive of X-linked SPG1.…”

Section: Neuroimaging Studiesmentioning

confidence: 99%

“…Progressive hydrocephalus due to aqueductal stenosis is highly suggestive of X-linked SPG1. White matter abnormalities may be found in some AR-HSP, such as SPG 5, SPG 21, SPG 35 or autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL) 47 . In SPG2, white matter abnormalities are also typical; they resemble (but to a lesser extent) the diffuse hypomyelination found in the allelic Pelizaeus-Merzbacher disease 25,48 (Figure 2).…”

Section: Neuroimaging Studiesmentioning

confidence: 99%

Clinical features and management of hereditary spastic paraplegia

Faber

Servelhere

Martínez

et al. 2014

Arq. Neuro-Psiquiatr.

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Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions. Keywords: hereditary spastic paraplegia, spastic paraplegia, muscle spasticity, genetics, mutation. RESUMOParaplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.Palavras-chave: paraplegia espástica hereditária, paraplegia espástica, espasticidade muscular, genética, mutação.

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“…Autosomal recessive spastic ataxias are a diverse group of neurodegenerative disorders caused by mutations in a variety of genes including SACS, 1 KIF1C, 2 MARS2, 3 and AFG3L2 4. These genes encode proteins with a variety of cellular functions, from the ubiquitin–proteasome system to axonal transport and protein translation.…”

Section: Introductionmentioning

confidence: 99%

GLS loss of function causes autosomal recessive spastic ataxia and optic atrophy

Lynch

Chelban

Vandrovcová

et al. 2018

Ann Clin Transl Neurol

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We describe a consanguineous family in which two brothers were affected by childhood onset spastic ataxia with optic atrophy and loss of motor and language skills. Through a combination of homozygosity mapping and whole‐genome sequencing, we identified a homozygous copy number variant in GLS as the cause. The duplication leads to complete knockout of GLS expression. GLS encodes the brain‐ and kidney‐specific enzyme glutaminase, which hydrolyzes glutamine for the production of glutamate, the most abundant central nervous system neurotransmitter. This is the first report implicating GLS loss of function in human disease.

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Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

Abstract: The study of Drosophila neurodegenerative mutants combined with genetic and biochemical analyses lead to the identification of multiple complex mutations in 60 patients with a novel form of ataxia/leukoencephalopathy.

Cited by 149 publications

References 94 publications

The life history of retrocopies illuminates the evolution of new mammalian genes

The life history of retrocopies illuminates the evolution of new mammalian genes

Clinical features and management of hereditary spastic paraplegia

GLS loss of function causes autosomal recessive spastic ataxia and optic atrophy

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