Incidental Mutation 'D4043:Ocrl'

• ID: 244
• Institutional Source: Beutler Lab
• Gene Symbol: Ocrl
• Ensembl Gene: ENSMUSG00000001173
• Gene Name: OCRL, inositol polyphosphate-5-phosphatase
• Synonyms: 9530014D17Rik, oculocerebrorenal syndrome of Lowe, OCRL1
• Essential gene?: Possibly non essential (E-score: 0.332)
• Stock #: D4043 (G3) of strain 483
• Status: Validated
• Chromosome: X
• Chromosomal Location: 47001264-47054745 bp(+) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): T to C at 47025200 bp (GRCm39)
• Zygosity: Homozygous
• Amino Acid Change: Valine to Alanine at position 359 (V359A)
• Ref Sequence: ENSEMBL: ENSMUSP00000110672
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000001202] [ENSMUST00000115020]
• AlphaFold: Q6NVF0
• Predicted Effect: probably benign; Transcript: ENSMUST00000001202; AA Change: V359A; PolyPhen 2 Score 0.440 (Sensitivity: 0.89; Specificity: 0.90)
• SMART Domains: Protein: ENSMUSP00000001202; Gene: ENSMUSG00000001173; AA Change: V359A

Domain	Start	End	E-Value	Type
Pfam:OCRL_clath_bd	18	118	1.5e-47	PFAM
low complexity region	168	189	N/A	INTRINSIC
IPPc	237	538	1.16e-147	SMART
Blast:RhoGAP	673	704	2e-11	BLAST
RhoGAP	731	895	4.93e-39	SMART

• Predicted Effect: probably benign; Transcript: ENSMUST00000115020; AA Change: V359A; PolyPhen 2 Score 0.440 (Sensitivity: 0.89; Specificity: 0.90)
• SMART Domains: Protein: ENSMUSP00000110672; Gene: ENSMUSG00000001173; AA Change: V359A

Domain	Start	End	E-Value	Type
PDB:2KIE|A	1	119	7e-69	PDB
low complexity region	168	189	N/A	INTRINSIC
IPPc	237	538	1.16e-147	SMART
PDB:2QV2|A	561	722	1e-97	PDB

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000142719
• Predicted Effect: probably benign; Transcript: ENSMUST00000154732
• SMART Domains: Protein: ENSMUSP00000122084; Gene: ENSMUSG00000001173

Domain	Start	End	E-Value	Type
Pfam:Exo_endo_phos	1	79	5.9e-6	PFAM
Blast:IPPc	139	175	5e-13	BLAST
PDB:3QBT|H	144	266	7e-83	PDB

• Meta Mutation Damage Score: 0.6454
• Coding Region Coverage:
  • 1x: 88.8%
  • 3x: 72.5%
• Validation Efficiency: 88% (220/249)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016] ; PHENOTYPE: Homozygous null mice do not develop and of the abnormalities associated with oculocerebrorenal syndrome of Lowe. [provided by MGI curators]
• Allele List at MGI:

  All alleles(6) : Targeted, knock-out(2) Gene trapped(4)

• Posted On: 2010-08-10

Nature of Mutation

DNA sequencing using the SOLiD technique identified a T to C transition at position 1273 of the Ocrl transcript in exon 12 of 24 total exons. Multiple transcripts of the Ocrl gene are displayed on Ensembl and Vega. The mutated nucleotide causes a valine to alanine substitution at amino acid 359 of the encoded protein. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Ocrl gene encodes a 900 amino acid protein that has mostly been characterized in humans (Uniprot Q6NVF0). In humans, the OCRL gene encodes a phosphatidylinositol 4,5-bisphosphate-5-phosphatase localized to the trans-Golgi network that is involved in actin polymerization. This protein may function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes. OCRL contains a Rho-GAP domain at the C-terminus (Uniprot Q01968). Mutations in the OCRL gene cause Lowe syndrome (OCRL; OMIM 309000), an X-linked multisystem disorder affecting eyes, nervous system, and kidney. It is characterized by hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, aminoaciduria, and reduced ammonia production by the kidney. OCRL mutations also cause Dent disease type (DD2; OMIM 300555) a renal disease characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. Homozygous null mice do not develop the abnormalities associated with Lowe syndrome, but mice doubly homozygous for mutations in Ocrl and Inpp5b, which encodes a highly homologous protein, display early embryonic lethality.

 

The V359A change is predicted to be possibly damaging by the PolyPhen program.