Alternative titles; symbols
HGNC Approved Gene Symbol: MPV17
SNOMEDCT: 784346006;
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38): 2:27,309,492-27,323,097 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | Charcot-Marie-Tooth disease, axonal, type 2EE | 618400 | Autosomal recessive | 3 |
| Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) | 256810 | Autosomal recessive | 3 |
The MPV17 gene encodes a mitochondrial inner membrane protein that is involved in mitochondrial deoxynucleotide homeostasis and maintenance of mtDNA (summary by Baumann et al., 2019).
The Mpv17 strain of mice carries a transgenically produced retroviral insert in its genome (Weiher et al., 1990). The integration prevents the expression of the Mpv17 gene, leading to the development of glomerulosclerosis in mice homozygous for the integration. Physiologically and histologically, the phenotype of the kidney disease resembles human glomerulosclerosis. The mice demonstrate nephrotic syndrome at an early age. Karasawa et al. (1993) isolated cDNA clones representing a single RNA species for the human MPV17 gene. Sequence analysis demonstrated over 90% identity to the mouse Mpv17 gene in the region coding for a protein of 176 amino acids and unknown function.
Spinazzola et al. (2006) detected MPV17 transcript in human pancreas, kidney, muscle, liver, lung, placenta, brain and heart.
Spinazzola et al. (2006) noted that the MPV17 gene has 7 exons.
Karasawa et al. (1993) used somatic cell hybrid analysis and in situ hybridization to map the MPV17 gene to chromosome 2p23-p21.
By Southern analysis of rodent/mouse somatic cell hybrids, Karasawa et al. (1993) demonstrated that the Mpv17 gene is located on mouse chromosome 5, thus defining a new region of homology between human 2p and mouse 5.
Dallabona et al. (2010) showed that the gene product of the S. cerevisiae ortholog of MPV17, Sym1, is essential to maintain oxidative phosphorylation (OXPHOS), glycogen storage, mitochondrial morphology, and mitochondrial DNA (mtDNA) stability in stressing conditions such as high temperature and ethanol-dependent growth. The authors identified and characterized multicopy suppressor genes and metabolic suppressor compounds. The authors concluded that (i) metabolic impairment and mtDNA instability occur independently as a consequence of Sym1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; and (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.
Choi et al. (2015) found that siRNA-mediated knockdown of the Mpv17 gene in murine motor neurons reduced cell proliferation and viability against reactive oxygen species (ROS) compared to controls. Knockdown also adversely affected mitochondrial integrity, as manifest by decreased OXPHOS levels.
Alonzo et al. (2018) found knockdown of MPV17 in HeLa cells resulted in a 30% reduction of mitochondrial FPGS (136510) and a 43% reduction of mitochondrial folate levels compared with control cells. Uracil levels in mitochondrial DNA were 3-fold higher in MPV17-knockdown cells compared with control cells.
Mitochondrial DNA Depletion Syndrome 6
In 3 families with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2006) identified a locus on chromosome 2p23-p21 and prioritized the genes on this locus using a new integrative genomic strategy. One of the top-scoring candidates was the MPV17 gene. They found disease-segregating MPV17 mutations (137960.0001-137960.0004) in the 3 families and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes failure of oxidative phosphorylation (OXPHOS) and mtDNA depletion in individuals with the hepatocerebral form of MTDPS and also in Mpv17 -/- mice.
MTDPS6 is also known as Navajo neurohepatopathy (NNH) because it had been described as a disorder prevalent in the Navajo population of the southwestern United States. Patients with NNH present with liver disease, severe sensory and motor neuropathy, corneal anesthesia and scarring, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent illness. The similarity of clinical, pathologic, and biochemical features seen in patients with NNH to those in patients with mtDNA depletion syndrome suggested that abnormal regulation of mtDNA copy number may be the primary defect in NNH. Supporting this suggestion was the finding of mtDNA depletion in liver biopsies from 2 patients with NNH (Vu et al., 2001). Both historical and demographic data from the Navajo population of a western Navajo reservation strongly suggested a founder effect as the origin of NNH. In this situation, homozygosity mapping is a powerful tool for the identification of the disease-causing gene. Karadimas et al. (2006) performed homozygosity mapping in 2 families with NNH and found a suggestion of linkage to chromosome 2p24. This locus included the MPV17 gene, which, when mutated, was known to cause the hepatocerebral form of mitochondrial DNA depletion. Sequencing of the MPV17 gene in 6 patients with NNH from 5 families, revealed the homozygous arg50-to-gln mutation (137960.0001), which had previously been described in a southern Italian family with hepatocerebral mtDNA depletion syndrome. Identification of a single missense mutation in patients with NNH corroborated the notion that the disease is due to a founder effect and extended the phenotypic spectrum associated with MPV17 mutations.
Charcot-Marie-Tooth Neuropathy, Type 2EE
In a 21-year-old Pakistani man with autosomal recessive Charcot-Marie-Tooth neuropathy type 2EE (CMT2EE; 618400), Blakely et al. (2012) identified a homozygous missense mutation in the MPV17 gene (P98L; 137960.0008). The mutation was found by direct sequencing of the MPV17 gene, but DNA from family members was not available for analysis. Functional studies of the variant were not performed.
In 2 unrelated Korean patients with CMT2EE, Choi et al. (2015) identified a homozygous missense mutation in the MPV17 gene (R41Q; 137960.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Transfection of the R41Q mutation into murine motor neurons inhibited cell proliferation, caused reduced of several OXPHOS proteins, and induced mtDNA depletion compared to controls.
Baumann et al. (2019) identified a homozygous R41Q mutation in the MPV17 gene in 2 Bosnian patients with CMT2EE. The mutation was found by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Three 3 Iraqi brothers from the religious minority of 'Jesidians' (Yazidis) in Northern Iraq with the disorder were found to have a homozygous splice site mutation in the MPV17 gene (137960.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The findings expanded the phenotype associated with biallelic MPV17 mutations.
In an Mpv17-knockout mouse model, Viscomi et al. (2009) found severe mtDNA depletion in liver and skeletal muscle, whereas hardly any depletion was detected in brain and kidney. Mouse embryonic fibroblasts only showed mtDNA depletion after several culturing passages or in serum-free medium. In spite of severe mtDNA depletion, only moderate decreases in respiratory chain enzymatic activities and mild cytoarchitectural alterations were observed in Mpv17 -/- livers, but neither cirrhosis nor failure ever occurred. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensation for the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf (602318), a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear, and kidney. The coat of the Mpv17 -/- mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter life span. Coincidental with the onset of FSGS, minimal mtDNA was measurable in glomerular tufts. Viscomi et al. (2009) concluded that Mpv17 controls mtDNA copy number by a highly tissue-specific and possibly cytotype-specific mechanism.
In affected members of a southern Italian family with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2006) found homozygosity for a 149G-A transition in exon 2 of the MPV17 gene, resulting in an arg50-to-gln (R50Q) substitution.
Karadimas et al. (2006) found the R50Q mutation as the basis of MTDPS6, also called Navajo neurohepatopathy because it was described as a founder disorder in the Navajo population of the southwestern United States.
In affected members of a consanguineous Moroccan family with mtDNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2006) identified homozygosity for a 498C-A transversion in exon 7 of the MPV17 gene, resulting in an asn166-to-lys (N166K) substitution.
In a child with mtDNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2006) found compound heterozygosity for 2 mutations in the MPV17 gene: a 148C-T transition in exon 2 of the MPV17 gene, resulting in an arg50-to-trp (R50W) substitution, and a 26-bp deletion (116-141del; 137960.0004).
For discussion of the 26-bp deletion in the MPV17 gene (116-141del) that was found in compound heterozygous state in a patient with mtDNA depletion syndrome-6 (MTDPS6; 256810) by Spinazzola et al. (2006), see 137960.0003.
In 2 sisters, born of consanguineous Iraqi parents, with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2008) identified a homozygous 359G-A transition in exon 5 of the MPV17 gene, resulting in a trp120-to-ter (W120X) substitution. Both died from rapidly progressive liver failure at ages 11 and 5 months, respectively.
In an infant girl with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), Spinazzola et al. (2008) identified compound heterozygosity for 2 mutations in the MPV17 gene: a G-to-T transversion resulting in a gly24-to-trp (G24W) substitution in the first transmembrane domain, and a 1.5-kb deletion encompassing intron 7 and part of exon 8 (137960.0007). She died of liver failure at age 9 months after developing neurologic signs.
For discussion of the 1.5-kb deletion in the MPV17 gene that was found in compound heterozygous state in a patient with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810) by Spinazzola et al. (2008), see 137960.0006.
In a 21-year-old Pakistani man with autosomal recessive Charcot-Marie-Tooth neuropathy type 2EE (CMT2EE; 618400), Blakely et al. (2012) identified a homozygous c.2898C-T transition (c.2898C-T, NM_002437.4) in the MPV17 gene, resulting in a pro98-to-leu (P98L) substitution at a highly conserved residue. The mutation was found by direct sequencing of MPV17 and 2 other genes implicated in mitochondrial DNA maintenance disorders with hepatocerebral involvement; DNA from family members was not available for analysis. Functional studies of the variant were not performed.
In 2 unrelated Korean patients with autosomal recessive Charcot-Marie-Tooth neuropathy type 2EE (CMT2EE; 618400), Choi et al. (2015) identified a homozygous c.122G-A transition in the MPV17 gene, resulting in an arg41-to-gln (R41Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The mutation was not found in the dbSNP (build 142) or 1000 Genomes Project databases, but was found at a low frequency in the Exome Sequencing Project (0.00008) and ExAC (0.00002471) databases. Transfection of the R41Q mutation into murine motor neurons inhibited cell proliferation, caused reduced of several OXPHOS proteins, and induced mtDNA depletion compared to controls.
Baumann et al. (2019) identified a homozygous R41Q mutation in the MPV17 gene in 2 Bosnian patients with CMT2EE. The mutation was found by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In 3 brothers from the religious minority of 'Jesidians' (Yazidis) in northern Iraq with autosomal recessive Charcot-Marie-Tooth neuropathy type 2EE (CMT2EE; 618400), Baumann et al. (2019) identified a homozygous T-to-G transversion in intron 5 of the MPV17 gene (c.376-9T-G), resulting in a splicing defect. RT-PCR analysis of patient cells showed that the mutation resulted in skipping of exon 6 in the majority of mRNAs, causing an in-frame deletion of 11 residues (Asp126_Tyr136del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the gnomAD database.
Alonzo, J. R., Venkataraman, C., Field, M. S., Stover, P. J. The mitochondrial inner membrane protein MPV17 prevents uracil accumulation in mitochondrial DNA. J. Biol. Chem. 293: 20285-20294, 2018. [PubMed: 30385507] [Full Text: https://doi.org/10.1074/jbc.RA118.004788]
Baumann, M., Schreiber, H., Schlotter-Weigel, B., Loscher, W. N., Stucka, R., Karall, D., Strom, T. M., Bauer, P., Krabichler, B., Fauth, C., Glaeser, D., Senderek, J. MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy. Clin. Genet. 95: 182-186, 2019. [PubMed: 30298599] [Full Text: https://doi.org/10.1111/cge.13462]
Blakely, E. L., Butterworth, A., Hadden, R. D. M., Bodi, I., He, L., McFarland, R., Taylor, R. W. MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle. Neuromusc. Disord. 22: 587-591, 2012. [PubMed: 22508010] [Full Text: https://doi.org/10.1016/j.nmd.2012.03.006]
Choi, Y.-R., Hong, Y. B., Jung, S.-C., Lee, J. H., Kim, Y. J., Park, H. J., Lee, J., Koo, H., Lee, J.-S., Jwa, D. H., Jung, N., Woo, S.-Y., Kim, S.-B., Chung, K. W., Choi, B.-O. A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy. BMC Neurol. 15: 179, 2015. Note: Electronic Article. [PubMed: 26437932] [Full Text: https://doi.org/10.1186/s12883-015-0430-1]
Dallabona, C., Marsano, R. M., Arzuffi, P., Ghezzi, D., Mancini, P., Zeviani, M., Ferrero, I., Donnini, C. Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator. Hum. Molec. Genet. 19: 1098-1107, 2010. [PubMed: 20042463] [Full Text: https://doi.org/10.1093/hmg/ddp581]
Karadimas, C. L., Vu, T. H., Holve, S. A., Chronopoulou, P., Quinzii, C., Johnsen, S. D., Kurth, J., Eggers, E., Palenzuela, L., Tanji, K., Bonilla, E., De Vivo, D. C., DiMauro, S., Hitano, M. Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Am. J. Hum. Genet. 79: 544-548, 2006. [PubMed: 16909392] [Full Text: https://doi.org/10.1086/506913]
Karasawa, M., Zwacka, R. M., Reuter, A., Fink, T., Hsieh, C. L., Lichter, P., Francke, U., Weiher, H. The human homolog of the glomerulosclerosis gene Mpv17: structure and genomic organization. Hum. Molec. Genet. 2: 1829-1834, 1993. [PubMed: 8281143] [Full Text: https://doi.org/10.1093/hmg/2.11.1829]
Spinazzola, A., Santer, R., Akman, O. H., Tsiakas, K., Schaefer, H., Ding, X., Karadimas, C. L., Shanske, S., Ganesh, J., Di Mauro, S., Zeviani, M. Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations. Arch. Neurol. 65: 1108-1113, 2008. [PubMed: 18695062] [Full Text: https://doi.org/10.1001/archneur.65.8.1108]
Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D'Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nature Genet. 38: 570-575, 2006. [PubMed: 16582910] [Full Text: https://doi.org/10.1038/ng1765]
Viscomi, C., Spinazzola, A., Maggioni, M., Fernandez-Vizarra, E., Massa, V., Pagano, C., Vettor, R., Mora, M., Zeviani, M. Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice. Hum. Molec. Genet. 18: 12-26, 2009. [PubMed: 18818194] [Full Text: https://doi.org/10.1093/hmg/ddn309]
Vu, T. H., Tanji, K., Holve, S. A., Bonilla, E., Sokol, R. J., Snyder, R. D., Fiore, S., Deutsch, G. H., DiMauro, S., De Vivo, D. Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome? Hepatology 34: 116-120, 2001. [PubMed: 11431741] [Full Text: https://doi.org/10.1053/jhep.2001.25921]
Weiher, H., Noda, T., Gray, D. A., Sharpe, A. H., Jaenisch, R. Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome. Cell 62: 425-434, 1990. [PubMed: 1696177] [Full Text: https://doi.org/10.1016/0092-8674(90)90008-3]