Home  |  Contact

UniProtKB/Swiss-Prot Q9UH77: Variant p.Leu387Pro

Kelch-like protein 3
Gene: KLHL3
Variant information

Variant position:  387
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 387 (L387P, p.Leu387Pro).
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:  Pseudohypoaldosteronism 2D (PHA2D) [MIM:614495]: A disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. PHA2D inheritance is autosomal dominant or recessive. {ECO:0000269|PubMed:22266938, ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031, ECO:0000269|PubMed:26435498, ECO:0000269|PubMed:27026694, ECO:0000269|PubMed:27780982, ECO:0000269|PubMed:28052936, ECO:0000269|PubMed:28511177}. 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 PHA2D; abolished interaction with WNK1.
Any additional useful information about the variant.

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



Sequence information

Variant position:  387
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  587
The length of the canonical sequence.

Location on the sequence:   YDGVKDQWTSIASMQERRST  L GAAVLNDLLYAVGGFDGSTG
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                         YDGVKDQWTSIASMQERRSTLGAAVLNDLLYAVGGFDGSTG

Mouse                         YDGVKDQWTSIASMQERRSTLGAAVLNDLLYAVGGFDGSTG

Rat                           YDGVKDQWTSIASMQERRSTLGAAVLNDLLYAVGGFDGSTG

Bovine                        YDGVKDQWTSIASMQERRSTLGAAVLNDLLYAVGGFDGSTG

Zebrafish                     YDGLKDQWSSIPSMQERRSTLGAAVLGDLLYAVGGFDGSTG

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 – 587 Kelch-like protein 3
Repeat 348 – 394 Kelch 2
Modified residue 375 – 375 Phosphothreonine
Modified residue 376 – 376 Phosphoserine


Literature citations

The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.
Ohta A.; Schumacher F.R.; Mehellou Y.; Johnson C.; Knebel A.; Macartney T.J.; Wood N.T.; Alessi D.R.; Kurz T.;
Biochem. J. 451:111-122(2013)
Cited for: FUNCTION; INTERACTION WITH CUL3; WNK1 AND WNK4; CHARACTERIZATION OF VARIANTS PHA2D GLU-77; VAL-78; ALA-85; PHE-164; ARG-309; VAL-340; GLN-384; PRO-387; LEU-410; ASN-432; ASN-433; THR-494; HIS-528; CYS-528 AND LYS-529;

Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.
Wu G.; Peng J.B.;
FEBS Lett. 587:1717-1722(2013)
Cited for: FUNCTION; INTERACTION WITH WNK4; CHARACTERIZATION OF VARIANTS PHA2D GLU-77; PHE-164; ARG-309; PRO-387 AND CYS-528;

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
Boyden L.M.; Choi M.; Choate K.A.; Nelson-Williams C.J.; Farhi A.; Toka H.R.; Tikhonova I.R.; Bjornson R.; Mane S.M.; Colussi G.; Lebel M.; Gordon R.D.; Semmekrot B.A.; Poujol A.; Valimaki M.J.; De Ferrari M.E.; Sanjad S.A.; Gutkin M.; Karet F.E.; Tucci J.R.; Stockigt J.R.; Keppler-Noreuil K.M.; Porter C.C.; Anand S.K.; Whiteford M.L.; Davis I.D.; Dewar S.B.; Bettinelli A.; Fadrowski J.J.; Belsha C.W.; Hunley T.E.; Nelson R.D.; Trachtman H.; Cole T.R.; Pinsk M.; Bockenhauer D.; Shenoy M.; Vaidyanathan P.; Foreman J.W.; Rasoulpour M.; Thameem F.; Al-Shahrouri H.Z.; Radhakrishnan J.; Gharavi A.G.; Goilav B.; Lifton R.P.;
Nature 482:98-102(2012)
Cited for: VARIANTS PHA2D GLU-77; VAL-78; ALA-85; PHE-164; ARG-309; CYS-322; ILE-336; VAL-340; GLN-384; PRO-387; LEU-410; THR-427; GLN-431; ASN-432; ASN-433; THR-494; THR-501; HIS-528; CYS-528; CYS-557 AND TRP-575; VARIANT ILE-438;

A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation.
Mitani M.; Furuichi M.; Narumi S.; Hasegawa T.; Chiga M.; Uchida S.; Sato S.;
Clin. Pediatr. Endocrinol. 25:127-134(2016)
Cited for: VARIANT PHA2D PRO-387;

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.