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UniProtKB/Swiss-Prot P50336: Variant p.Leu154Pro

Protoporphyrinogen oxidase
Gene: PPOX
Variant information

Variant position:  154
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 Leucine (L) to Proline (P) at position 154 (L154P, p.Leu154Pro).
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:  Variegate porphyria (VP) [MIM:176200]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:10870850, ECO:0000269|PubMed:11074242, ECO:0000269|PubMed:11102990, ECO:0000269|PubMed:11286631, ECO:0000269|PubMed:11348478, ECO:0000269|PubMed:11350188, ECO:0000269|PubMed:11474578, ECO:0000269|PubMed:12380696, ECO:0000269|PubMed:12655566, ECO:0000269|PubMed:12859407, ECO:0000269|PubMed:12922165, ECO:0000269|PubMed:14669009, ECO:0000269|PubMed:16433813, ECO:0000269|PubMed:16621625, ECO:0000269|PubMed:16922948, ECO:0000269|PubMed:16947091, ECO:0000269|PubMed:18350656, ECO:0000269|PubMed:18570668, ECO:0000269|PubMed:19320019, ECO:0000269|PubMed:21048046, ECO:0000269|PubMed:23430901, ECO:0000269|PubMed:23467411, ECO:0000269|PubMed:24073655, ECO:0000269|PubMed:8673113, ECO:0000269|PubMed:8817334, ECO:0000269|PubMed:8852667, ECO:0000269|PubMed:9541112, ECO:0000269|PubMed:9763307, ECO:0000269|PubMed:9811936}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations leading to severe PPOX deficiency cause the rare homozygous variant form of VP. Missense mutations that preserve 10%-25% of wild-type activity may not cause clinically overt VP in heterozygotes (PubMed:9811936). Mutations with intermediate effect on catalytic activity may cause VP, but with a low clinical penetrance (PubMed:10486317). {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:9811936}.
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 VP; strongly decreases enzyme activity.
Any additional useful information about the variant.



Sequence information

Variant position:  154
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  477
The length of the canonical sequence.

Location on the sequence:   LTKPRGKEPDETVHSFAQRR  L GPEVASLAMDSLCRGVFAGN
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                         LTKP-----RGKEP--DETVHSFAQRRLGPE-VASLAMDSLCRGVFAGN

Mouse                         LLKP-----RGKEP--DETVHSFAQRRLGPE-VASLAMDSL

Bovine                        LTTP-----RGKDP--DETVHSFAQRRLGPE-VASLAMDSL

Slime mold                    PFKKVPSQVKEMDPNWDESVHDFFSRRLGKT-MTKTFIEPT

Baker's yeast                 WFRK-----KSPHPGQDESVESICDRRFGNNYISNNMISAL

Fission yeast                 PFR------KSKRDSTDESVGSFMRRRFGKN-VTDRVMSAM

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 – 477 Protoporphyrinogen oxidase
Mutagenesis 166 – 166 L -> N. Decreases enzyme activity by 95%.
Mutagenesis 169 – 169 G -> A. Decreases enzyme activity by 64%.
Helix 146 – 154


Literature citations

Structural insight into human variegate porphyria disease.
Qin X.; Tan Y.; Wang L.; Wang Z.; Wang B.; Wen X.; Yang G.; Xi Z.; Shen Y.;
FASEB J. 25:653-664(2011)
Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH FAD AND ACIFLUORFEN; CATALYTIC ACTIVITY; FUNCTION; SUBUNIT; CHARACTERIZATION OF VARIANTS VP ASP-11; THR-12; PHE-15; PRO-20; PRO-38; ALA-40; GLU-40; TRP-59; PRO-73; GLY-84; PRO-85; PRO-106; PRO-138; ASP-139; VAL-143; CYS-152; PRO-154; MET-158; HIS-168; VAL-178; VAL-205; CYS-217; GLY-224; ARG-232; ASP-282; ASN-283; PRO-295; ARG-330; ALA-332; GLY-335; CYS-348; ALA-349; PRO-350; ARG-358; ASP-397; PHE-401; PRO-433; PRO-444; ARG-448; PRO-450 AND ARG-453; MUTAGENESIS OF LEU-74; ARG-97; LEU-166; GLY-169; SER-284; VAL-290; PHE-331; LEU-334; VAL-347 AND MET-368;

Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation.
Whatley S.D.; Puy H.; Morgan R.R.; Robreau A.M.; Roberts A.G.; Nordmann Y.; Elder G.H.; Deybach J.C.;
Am. J. Hum. Genet. 65:984-994(1999)
Cited for: VARIANTS ARG-256 AND HIS-304; VARIANTS VP PRO-38; GLU-40; PRO-73; GLY-84; PRO-85; VAL-143; CYS-152; PRO-154; MET-158; HIS-168; VAL-172; ARG-232; HIS-281 DEL; ASP-282; PRO-295; GLY-335; PRO-350; PRO-444; ARG-453 AND VAL-453;

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.