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UniProtKB/Swiss-Prot P39210: Variant p.Pro98Leu

Protein Mpv17
Gene: MPV17
Variant information

Variant position:  98
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Proline (P) to Leucine (L) at position 98 (P98L, p.Pro98Leu).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Similar physico-chemical property. Both residues are medium size and hydrophobic.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Charcot-Marie-Tooth disease, axonal, 2EE (CMT2EE) [MIM:618400]: A recessive axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2EE is a slowly progressive, sensorimotor peripheral axonal neuropathy with onset in the first or second decades of life. The disorder primarily affects the lower limbs, sometimes resulting in loss of ambulation, with later onset of upper limb involvement. {ECO:0000269|PubMed:22508010, ECO:0000269|PubMed:24190800, ECO:0000269|PubMed:26437932, ECO:0000269|PubMed:30298599}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in disease:  Mitochondrial DNA depletion syndrome 6 (MTDPS6) [MIM:256810]: A disease due to mitochondrial dysfunction. It is characterized by infantile onset of progressive liver failure, often leading to death in the first year of life, peripheral neuropathy, corneal scarring, acral ulceration and osteomyelitis leading to autoamputation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. {ECO:0000269|PubMed:16582907, ECO:0000269|PubMed:16582910, ECO:0000269|PubMed:16909392, ECO:0000269|PubMed:17694548, ECO:0000269|PubMed:18695062, ECO:0000269|PubMed:19520594, ECO:0000269|PubMed:20074988, ECO:0000269|PubMed:23714749, ECO:0000269|PubMed:23829229, ECO:0000269|PubMed:25129007, ECO:0000269|PubMed:25861990, ECO:0000269|PubMed:26741492, ECO:0000269|PubMed:27536553, ECO:0000269|PubMed:28207748, ECO:0000269|PubMed:29282788, ECO:0000269|PubMed:30833296}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In MTDPS6 and CMT2EE; results in incomplete closing of the channel.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  98
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  176
The length of the canonical sequence.

Location on the sequence:   PGTTKVDALKKMLLDQGGFA  P CFLGCFLPLVGALNGLSAQD
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         PGTTKVD--ALKKMLLDQGGFAPCFLGCFLPLVGALNGLSAQD

Mouse                         PGTTKVH--ALKKMLLDQGGFAPCFLGCFLPLVGILNGMSA

Rat                           PGTTKVN--ALKKMLLDQGGFAPCFLGCFLPLVGVLNGMSA

Bovine                        PGTTKVD--ALKKMLLDQGGFAPCFLGCFLPLVGTLNGLSA

Xenopus laevis                PGSGKPV--ALKKMLLDQVAFAPCFLGCFLSIASALNGLSG

Zebrafish                     TGGTKSA--ALKKMLVDQVGFAPCFLGAFLGITGTLNGLTV

Caenorhabditis elegans        GNNKSLL--LVKKLCIDQLCFSPCFNAAILFNLRLLQHQSA

Drosophila                    PKTYSPMRRGVTKMLVDQTLFAPPFTMAMSFLVPLSNGEPI

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 176 Protein Mpv17
Transmembrane 94 – 114 Helical
Site 92 – 92 Determines ion selectivity
Mutagenesis 80 – 80 T -> A. Does not affect gating properties of the channel.
Mutagenesis 92 – 92 D -> K. Affects ion selectivity of the channel.
Mutagenesis 99 – 99 C -> A. Does not affect conductance and gating properties of the channel.


Literature citations

The human mitochondrial DNA depletion syndrome gene MPV17 encodes a non-selective channel that modulates membrane potential.
Antonenkov V.D.; Isomursu A.; Mennerich D.; Vapola M.H.; Weiher H.; Kietzmann T.; Hiltunen J.K.;
J. Biol. Chem. 290:13840-13861(2015)
Cited for: FUNCTION; MUTAGENESIS OF THR-80; ASP-92 AND CYS-99; CHARACTERIZATION OF VARIANT MTDPS6 LEU-98;

MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations.
El-Hattab A.W.; Li F.Y.; Schmitt E.; Zhang S.; Craigen W.J.; Wong L.J.;
Mol. Genet. Metab. 99:300-308(2010)
Cited for: VARIANTS MTDPS6 GLN-50; GLU-88; LYS-88 DEL; LEU-91 DEL; ARG-94; LEU-98 AND ASP-162;

MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle.
Blakely E.L.; Butterworth A.; Hadden R.D.; Bodi I.; He L.; McFarland R.; Taylor R.W.;
Neuromuscul. Disord. 22:587-591(2012)
Cited for: VARIANT CMT2EE LEU-98;

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.
Uusimaa J.; Evans J.; Smith C.; Butterworth A.; Craig K.; Ashley N.; Liao C.; Carver J.; Diot A.; Macleod L.; Hargreaves I.; Al-Hussaini A.; Faqeih E.; Asery A.; Al Balwi M.; Eyaid W.; Al-Sunaid A.; Kelly D.; van Mourik I.; Ball S.; Jarvis J.; Mulay A.; Hadzic N.; Samyn M.; Baker A.; Rahman S.; Stewart H.; Morris A.A.; Seller A.; Fratter C.; Taylor R.W.; Poulton J.;
Eur. J. Hum. Genet. 22:184-191(2014)
Cited for: VARIANTS MTDPS6 ARG-21; PRO-23; PRO-36; TRP-41; 44-GLN--LEU-176 DEL; ARG-64; PRO-93 AND LEU-98;

Mitochondrial DNA depletion syndrome causing liver failure.
Bijarnia-Mahay S.; Mohan N.; Goyal D.; Verma I.C.;
Indian Pediatr. 51:666-668(2014)
Cited for: VARIANTS MTDPS6 LEU-98 AND 136-TYR--LEU-176 DEL;

Adult-onset fatal neurohepatopathy in a woman caused by MPV17 mutation.
Mendelsohn B.A.; Mehta N.; Hameed B.; Pekmezci M.; Packman S.; Ralph J.;
JIMD Rep. 13:37-41(2014)
Cited for: VARIANT CMT2EE LEU-98;

MPV17 mutations in patients with hepatocerebral mitochondrial DNA depletion syndrome.
Kim J.; Kang E.; Kim Y.; Kim J.M.; Lee B.H.; Murayama K.; Kim G.H.; Choi I.H.; Kim K.M.; Yoo H.W.;
Mol. Genet. Metab. Rep. 8:74-76(2016)
Cited for: VARIANTS MTDPS6 GLU-66; ARG-94 AND LEU-98;

A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies.
Kohda M.; Tokuzawa Y.; Kishita Y.; Nyuzuki H.; Moriyama Y.; Mizuno Y.; Hirata T.; Yatsuka Y.; Yamashita-Sugahara Y.; Nakachi Y.; Kato H.; Okuda A.; Tamaru S.; Borna N.N.; Banshoya K.; Aigaki T.; Sato-Miyata Y.; Ohnuma K.; Suzuki T.; Nagao A.; Maehata H.; Matsuda F.; Higasa K.; Nagasaki M.; Yasuda J.; Yamamoto M.; Fushimi T.; Shimura M.; Kaiho-Ichimoto K.; Harashima H.; Yamazaki T.; Mori M.; Murayama K.; Ohtake A.; Okazaki Y.;
PLoS Genet. 12:E1005679-E1005679(2016)
Cited for: VARIANT MTDPS6 LEU-98;

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.
El-Hattab A.W.; Wang J.; Dai H.; Almannai M.; Staufner C.; Alfadhel M.; Gambello M.J.; Prasun P.; Raza S.; Lyons H.J.; Afqi M.; Saleh M.A.M.; Faqeih E.A.; Alzaidan H.I.; Alshenqiti A.; Flore L.A.; Hertecant J.; Sacharow S.; Barbouth D.S.; Murayama K.; Shah A.A.; Lin H.C.; Wong L.C.;
Hum. Mutat. 39:461-470(2018)
Cited for: VARIANTS MTDPS6 ARG-21; TRP-50; LYS-88 DEL; LEU-91 DEL; GLY-92; PRO-93; ASP-95; LEU-98; 99-CYS--LEU-176 DEL AND MET-154;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.