Mutations in theMPV17 gene are responsible for rapidly progressive liver failure in infancy

Wong, Lee Jun; Brunetti‐Pierri, Nicola; Zhang, Qing; Yazigi, Nada; Bove, Kevin E.; Dahms, Beverly B.; Puchowicz, Michelle A.; González-Gómez, Ignacio; Schmitt, Éric; Truong, Cavatina K.; Hoppel, Charles L.; Chou, Ping-Chieh; Wang, Jing; Baldwin, Erin E.; Adams, Darius; Leslie, Nancy; Boles, Richard G.; Kerr, Douglas S.; Craigen, William J.

doi:10.1002/hep.21799

Cited by 115 publications

(114 citation statements)

References 20 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…1A). Both human MPV17 and yeast Sym1 have been localized to the inner mitochondrial membrane and display similar membrane topologies, with four predicted transmembrane spans (63,65,77). For biochemical characterization of Sym1, we generated a yeast strain (SYM1 ZZ ) expressing Sym1 from its own promoter, which was fused to two repeats of the IgG-binding domain of protein A (the Z domain) followed by a polyhistidine tag at its C terminus.…”

Section: Resultsmentioning

confidence: 99%

The Channel-Forming Sym1 Protein Is Transported by the TIM23 Complex in a Presequence-Independent Manner

Reinhold

Krüger

Meinecke

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

fThe majority of multispanning inner mitochondrial membrane proteins utilize internal targeting signals, which direct them to the carrier translocase (TIM22 complex), for their import. MPV17 and its Saccharomyces cerevisiae orthologue Sym1 are multispanning inner membrane proteins of unknown function with an amino-terminal presequence that suggests they may be targeted to the mitochondria. Mutations affecting MPV17 are associated with mitochondrial DNA depletion syndrome (MDDS). Reconstitution of purified Sym1 into planar lipid bilayers and electrophysiological measurements have demonstrated that Sym1 forms a membrane pore. To address the biogenesis of Sym1, which oligomerizes in the inner mitochondrial membrane, we studied its import and assembly pathway. Sym1 forms a transport intermediate at the translocase of the outer membrane (TOM) complex. Surprisingly, Sym1 was not transported into mitochondria by an amino-terminal signal, and in contrast to what has been observed in carrier proteins, Sym1 transport and assembly into the inner membrane were independent of small translocase of mitochondrial inner membrane (TIM) and TIM22 complexes. Instead, Sym1 required the presequence of translocase for its biogenesis. Our analyses have revealed a novel transport mechanism for a polytopic membrane protein in which internal signals direct the precursor into the inner membrane via the TIM23 complex, indicating a presequence-independent function of this translocase.

show abstract

Section: Resultsmentioning

confidence: 99%

The Channel-Forming Sym1 Protein Is Transported by the TIM23 Complex in a Presequence-Independent Manner

Reinhold

Krüger

Meinecke

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Approximately 30 affected individuals have been reported with MPV17-related hepatocerebral MDS [59][60][61][62][63][64][65][66][67][68]. Of note, among those confirmed cases are individuals with Navajo neurohepatopathy who were found to have homozygous p.Arg50Gln mutations in MPV17.…”

Section: Mpv17-related Hepatocerebral Mdsmentioning

confidence: 99%

“…Less frequent manifestations include renal tubulopathy, hypoparathyroidism, and gastrointestinal dysmotility that manifests as gastroesophageal reflux, cyclic vomiting, and diarrhea. Corneal anesthesia and ulcers were reported in individuals homozygous for the mutation p.Arg50Gln [59][60][61][62][63][64][65][66][67][68].…”

Section: Mpv17-related Hepatocerebral Mdsmentioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

View full text Add to dashboard Cite

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2,

show abstract

“…MDDSs cause a reduction in cellular mtDNA content (2 ). At the present time, mutations in at least 9 genes [POLG, 4 polymerase (DNA directed), gamma; DGUOK, deoxyguanosine kinase; TK2, thymidine kinase, mitochondrial; TYMP, thymidine phosphorylase; MPV17, MpV17 mitochondrial inner membrane protein; SUCLA2, succinate-CoA ligase, ADP-forming, beta subunit; SUCLG1, succinate-CoA ligase, alpha sub-unit; RRM2B, ribonucleotide reductase M2 B (TP53 inducible); C10orf2, chromosome 10 open reading frame 2 (also known as TWINKLE)] have been found to cause mtDNA depletion (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Quantitative Evaluation of the Mitochondrial DNA Depletion Syndrome

et al. 2010

View full text Add to dashboard Cite

Background: The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a reduction in cellular mtDNA content. Mutations in at least 9 genes [POLG, polymerase (DNA directed), gamma; DGUOK, deoxyguanosine kinase; TK2, thymidine kinase, mitochondrial; TYMP, thymidine phosphorylase; MPV17, MpV17 mitochondrial inner membrane protein; SUCLA2, succinate-CoA ligase, ADP-forming, beta subunit; SUCLG1, succinate-CoA ligase, alpha subunit; RRM2B, RRM2B, ribonucleotide reductase M2 B (TP53 inducible); and C10orf2, chromosome 10 open reading frame 2 (also known as TWINKLE)] have been reported to cause mtDNA depletion. In the clinical setting, a simple method to quantify mtDNA depletion would be useful before undertaking gene sequence analysis. Methods: Real-time quantitative PCR (qPCR) was used to measure the mtDNA content in blood, muscle, and liver samples and in skin fibroblast cultures from individuals suspected of mitochondrial disorders, with or without deleterious mutations in genes responsible for MDDS. Results: The mtDNA content was quantified in 776 tissue samples (blood, n = 341; muscle, n = 325; liver, n = 63; skin fibroblasts, n = 47) from control individuals. mtDNA content increased with age in muscle tissue, decreased with age in blood samples, and appeared to be unaffected by age in liver samples. In 165 samples (blood, n = 122; muscle, n = 21; liver, n = 15; skin fibroblasts, n = 7) from patients with molecularly proven MDDSs, severe mtDNA depletion was detected in liver and muscle tissue with high specificity and sensitivity. Blood samples were specific but not sensitive for detecting mtDNA depletion, and skin fibroblasts were not valuable for evaluating mtDNA depletion. Mutations in the POLG, RRM2B, and MPV17 genes were prospectively identified in 1 blood, 1 liver, and 3 muscle samples. Conclusions: Muscle and liver tissues, but not blood or skin fibroblasts, are potentially useful for rapid screening for mtDNA depletion with real-time qPCR.

show abstract

Mutations in theMPV17 gene are responsible for rapidly progressive liver failure in infancy

Abstract: We therefore propose that mutations in the MPV17 gene be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure.

Cited by 115 publications

References 20 publications

The Channel-Forming Sym1 Protein Is Transported by the TIM23 Complex in a Presequence-Independent Manner

The Channel-Forming Sym1 Protein Is Transported by the TIM23 Complex in a Presequence-Independent Manner

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

Quantitative Evaluation of the Mitochondrial DNA Depletion Syndrome

Contact Info

Product

Resources

About