A novel<i>HSD17B10</i>mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

Falk, Marni J.; Gai, Xiaowu; Shigematsu, Megumi; Vilardo, Elisa; Takase, Ryuichi; McCormick, Elizabeth; Christian, Tom; Place, Emily; Pierce, Eric A.; Consugar, Mark; Gamper, Howard; Rossmanith, Walter; Hou, Ya‐Ming

doi:10.1080/15476286.2016.1159381

Cited by 43 publications

(46 citation statements)

References 52 publications

(90 reference statements)

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“…Consistent with our hypothesis, the ratio of MRPP1/2 to MRPP3 needed to obtain maximal STO activity (kmax,app) is variable ( Figure 2B and 2C). These data show that the stoichiometry of MRPP subunits (MRPP1:2:3) to achieve the maximal activity is not a simple 2:4:1 ratio, as commonly concluded in previous reports (13,14,18,(24)(25)(26).…”

Section: Mrpp3 Recognizes Mrpp1/2-pre-trna As Cosubstratesupporting

confidence: 82%

“…We chose this substrate so we can compare the kinetics of MRPP1/2/3 with PRORP1. STO kinetics and MTO activity with only a single time-point have been previously described for human mtRNase P (13,14,23,24,29). Here, we present the first detailed MTO kinetic analysis.…”

Section: Mrpp1/2 Enhances Pre-trna Cleavage Catalyzed By Mrpp3mentioning

confidence: 88%

“…MRPP1, 2, and 3 are required for the proper processing of mitochondrial transcripts in vivo, including transcripts that encode for respiratory chain complexes. Disruption of these processes leads to mitochondrial dysfunction and disease (14)(15)(16)(17). Recessive MRPP1 mutations destabilize the mutant protein and lead to inadequate processing of mt-tRNA and low levels of assembled respiratory chain complexes (15).…”

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confidence: 99%

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Kinetic mechanism of human mitochondrial RNase P

Liu

Shanmuganathan

et al. 2019

Preprint

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A first step in processing mitochondrial precursor tRNA (pre-tRNA) is cleavage of the 5' leader catalyzed by ribonuclease P (RNase P). Human mitochondrial RNase P (mtRNase P) is composed of three protein subunits: mitochondrial RNase P protein (MRPP) 1, 2 and 3. Even though MRPP3 is the metallonuclease subunit responsible for catalysis, cleavage is observed only in the presence of the MRPP1/2 subcomplex. To understand the functional role of MRPP1/2, we reconstituted human mitochondrial RNase P in vitro and performed kinetic and thermodynamic analyses. MRPP1/2 significantly enhances both the catalytic activity and the apparent substrate affinity of mtRNase P. Additionally, pull-down and binding data demonstrate synergy between binding pre-tRNA and formation of a catalytically active MRPP1/2/3 complex. These data suggest that conformational changes in the MRPP1/2-pre-tRNA complex lead to protein-protein or protein-RNA interactions that increase both MRPP3 recognition and cleavage efficiency. This work presents the first kinetic model for human mtRNase P, providing a fundamental framework for the function of † The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

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Section: Mrpp3 Recognizes Mrpp1/2-pre-trna As Cosubstratesupporting

confidence: 82%

Section: Mrpp1/2 Enhances Pre-trna Cleavage Catalyzed By Mrpp3mentioning

confidence: 88%

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confidence: 99%

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Kinetic mechanism of human mitochondrial RNase P

Liu

Shanmuganathan

et al. 2019

Preprint

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“…However, while there is strong functional evidence that it does cause MHBD deficiency, the evidence linking p.Leu122Val to significantly deleterious effects on mitochondrial function is less compelling. Our patients clearly do have a biochemical disorder of isoleucine metabolism, but this in itself is no longer considered clinically important (Chatfield et al, ; Deutschmann et al, ; Falk et al, ; Rauschenberger et al, ; Vilardo & Rossmanith, ). It is less certain that our patients genuinely have “HSD10 mitochondrial disease, ” in the sense of a clinically significant disease involving deficient mitochondrial respiratory chain function.…”

Section: Discussionmentioning

confidence: 99%

HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French‐Canadian patients from Quebec

Waters

Lāce

Buhaş

et al. 2019

Molec Gen & Gen Med

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BackgroundHSD10 mitochondrial disease (HSD10MD), originally described as a deficiency of 2‐methyl‐3‐hydroxybutyryl‐CoA dehydrogenase (MHBD), is a rare X‐linked disorder of a moonlighting protein encoded by the HSD17B10. The diagnosis is usually first suspected on finding elevated isoleucine degradation metabolites in urine, reflecting decreased MHBD activity. However, it is now known that clinical disease pathogenesis reflects other independent functions of the HSD10 protein; particularly its essential role in mitochondrial transcript processing and tRNA maturation. The classical phenotype of HSD10MD in affected males is an infantile‐onset progressive neurodegenerative disorder associated with severe mitochondrial dysfunction.Patients, Methods, and ResultsIn four unrelated families, we identified index patients with MHBD deficiency, which implied a diagnosis of HSD10MD. Each index patient was independently investigated because of neurological or developmental concerns. All had persistent elevations of urinary 2‐methyl‐3‐hydroxybutyric acid and tiglylglycine. Analysis of HSD17B10 identified a single missense variant, c.364C>G, p.Leu122Val, in each case. This rare variant (1/183336 alleles in gnomAD) was previously reported in one Dutch patient and was described as pathogenic. The geographic origins of our families and results of haplotype analysis together provide evidence of a founder effect for this variant in Quebec. Notably, we identified an asymptomatic hemizygous adult male in one family, while a second independent genetic disorder contributed substantially to the clinical phenotypes observed in probands from two other families.ConclusionThe phenotype associated with p.Leu122Val in HSD17B10 currently appears to be attenuated and nonprogressive. This report widens the spectrum of phenotypic severity of HSD10MD and contributes to genotype–phenotype correlation. At present, we consider p.Leu122Val a “variant of uncertain significance.” Nonetheless, careful follow‐up of our patients remains advisable, to assess long‐term clinical course and ensure appropriate management. It will also be important to identify other potential patients in our population and to characterize their phenotype.

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“…Disturbance of 5' end pre-tRNA processing is indicated in several mitochondrial diseases, such us maternally inherited essential hypertension, mitochondrial myopathy, MELAS and HSD10 disease (Bindoff et al, 1993;Chatfield et al, 2015b;Deutschmann et al, 2014a;Falk et al, 2016;Li and Guan, 2010;Rossmanith and Karwan, 1998;Vilardo and Rossmanith, 2015;Wang et al, 2011). Mitochondrial diseases can be inherited in two ways, either by mendelian mutations in the nuclear genome or mutations in the mitochondrial genome.…”

Section: Introductionmentioning

confidence: 99%

Disease associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation and tRNA processing by mtRNase P

Karasik¹,

Fierke

Koutmos

2020

Preprint

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ABSTRACTMitochondrial diseases linked to mutations in mitochondrial(mt) tRNA sequences are abundant. However, the contributions of these tRNA mutations to the development of diseases is mostly unknown. Mutations may affect interactions with (mt)tRNA maturation enzymes or protein synthesis machinery leading to mitochondrial dysfunction. In human mitochondria, the first step of tRNA processing is the removal of the 5’end of precursor tRNAs (pre-tRNA) catalyzed by the three-component enzyme, mtRNase P. Additionally, one sub-component of mtRNase P, mitochondrial RNase P protein 1 (MRPP1) catalyzes methylation of the R9 base in pre-tRNAs. Despite the central role of 5’ end processing in mitochondrial tRNA maturation, the link between mtRNase P and diseases is mostly unexplored. Here we investigate how 11 different human disease-linked mutations in (mt)pre-tRNAs affect the activities of mtRNase P. We find that several mutations weaken the pre-tRNA binding affinity, while the majority of mutations decrease 5’ end processing and methylation activity catalyzed by mtRNase P. Furthermore, all of the investigated mutations in (mt)pre-tRNALeu(UUR) alter the tRNA fold which contributes to the partial loss of function of mtRNase P. Overall, these results reveal an etiological link between early steps of (mt)tRNA-substrate processing and mitochondrial disease.

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A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

Cited by 43 publications

References 52 publications

Kinetic mechanism of human mitochondrial RNase P

Kinetic mechanism of human mitochondrial RNase P

HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French‐Canadian patients from Quebec

Disease associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation and tRNA processing by mtRNase P

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