Strain Name:
STOCK Inpp5btm2Nbm Ocrltm1Nbm Tg(INPP5B)CNbm/Mmucd
Stock Number:
050927-UCD
Citation ID:
RRID:MMRRC_050927-UCD
Other Names:
Lowe Mice or Lowe Syndrome Mice

Strain Information

Inpp5btm2Nbm
Name: inositol polyphosphate-5-phosphatase B; targeted mutation 2, Robert L Nussbaum
Synonyms: Inpp5bflox
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 4
Alteration at locus: Conditional
Inpp5b
Name: inositol polyphosphate-5-phosphatase B
Synonyms: 75kDa
Type: Gene
Species: Mouse
Chromosome: 4
Alteration at locus: Conditional
NCBI: 16330
HGNC: HGNC:6077
Homologene: 69021
Ocrltm1Nbm
Name: OCRL, inositol polyphosphate-5-phosphatase; targeted mutation 1, Robert L Nussbaum
Synonyms: Ocrl1neo, Ocrl1-
Type: Allele
Species: Mus musculus (mouse)
Chromosome: X
Alteration at locus: Knockout
Ocrl
Name: OCRL, inositol polyphosphate-5-phosphatase
Synonyms: OCRL1, 9530014D17Rik, oculocerebrorenal syndrome of Lowe
Type: Gene
Species: Mus musculus (mouse)
Chromosome: X
Alteration at locus: Knockout
NCBI: 320634
HGNC: HGNC:8108
Homologene: 233
Tg(INPP5B)CNbm
Name: transgene insertion C, Robert L Nussbaum
Type: Allele
Species: Homo sapiens (human)
Chromosome: unknown
Alteration at locus: Transgenic (random, gene disruption)
INPP5B
Name: inositol polyphosphate-5-phosphatase B
Type: Gene
Species: Homo sapiens (human)
Chromosome: 1
Alteration at locus: Transgenic (random, gene disruption)
Genetic Alterations
Total of 3 mutations:
  1. Ocrltm1Nbm - OCRL, inositol polyphosphate-5-phosphatase (MGI:109589): Constitutive knockout of the Ocrl gene by inserting an in-frame stop codon in exon 19. X-linked.
  2. Inpp5btm2Nbm - inositol polyphosphate-5-phosphatase B (MGI:103257): Insertion of a neomycin resistance cassette into an intron downstream of exon 15 placed a loxP site at the 3' end of the neo cassette and introduced a second loxP site in an intron upstream of exon 15. This allele is still floxed.
  3. Tg(INPP5B)CNbm: Pronuclear microinjection of a bacterial artificial chromosome containing the human INPP5B gene (BAC RP11-431J04). Data suggests insertion in multiple tandem copies in an unknown location of the mouse genome. Not sex-linked, always homozygous.
Since CCE/EK.CCE ES cells were used during the development, it is possible that the Gpi1c allele (glucose phosphate isomerase 1; c variant - MGI:2177272) is still present. Additional information is available in ExPASY - Cellosaurus (CVCL-C313) and in PMID:7242681.
Genotype Determination
ES Cell Line
TC1/TC-1 derived from 129S6/SvEvTac
Phenotype
These mice exhibit symptoms of Lowe oculocerebrorenal syndrome and Dent Disease 2 tubulopathy with reduced postnatal growth, low molecular weight proteinuria, and aminoaciduria. Homozygotes (Ocrl KO, Inpp5b floxed, INPP5B KI) are viable and fertile, though the pups are often smaller than wildtype C57BL/6J pups of the same age. They come in three coat colors (white, agouti, and black) due to their genetic background (129/Sv, FVB/N, C57BL/6 mixed background = STOCK).
Mammalian Phenotype Terms
Allelic Composition: (Genetic Background: )

MeSH Terms
  • Animals
  • Dent Disease/genetics
  • Disease Models, Animal
  • Female
  • Genotype
  • Kidney Tubules/physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Oculocerebrorenal Syndrome/genetics
  • Phosphoric Monoester Hydrolases/genetics
  • Breeding
  • Calibration
  • Crosses, Genetic
  • Embryo Loss/genetics
  • Heterozygote
  • Phosphoric Monoester Hydrolases/deficiency
  • Phosphoric Monoester Hydrolases/metabolism
  • X Chromosome Inactivation/genetics
  • Amino Acid Sequence
  • Amino Acids/urine
  • Gene Expression/genetics
  • Gene Targeting
  • Humans
  • Inositol Polyphosphate 5-Phosphatases
  • Molecular Sequence Data
  • Motor Activity/physiology
  • Oculocerebrorenal Syndrome/physiopathology
  • Phenotype
  • Phosphoric Monoester Hydrolases/physiology
  • Proteins/genetics
  • Proteins/physiology
  • RNA Splicing
  • RNA, Messenger/metabolism
  • Stem Cells
  • ADAM Proteins
  • Fertilins
  • Fertilization in Vitro
  • Infertility, Male/enzymology
  • Infertility, Male/genetics
  • Infertility, Male/pathology
  • Infertility, Male/physiopathology
  • Membrane Glycoproteins/metabolism
  • Metalloendopeptidases/metabolism
  • Protein Processing, Post-Translational
  • Sperm Count
  • Sperm Motility/genetics
  • Sperm Motility/physiology
  • Spermatogenesis/genetics
  • Spermatogenesis/physiology
  • Spermatozoa/enzymology
  • Spermatozoa/growth & development
  • Spermatozoa/physiology
Strain Development
Three mouse lines were crossed to generate the Lowe Syndrome Mice.

  1. Ocrl-deficient mice:
    Targeting vector with sequence homology to the 3’-end of Ocrl flanking a complete PGK-neo cassette with DT-A for negative selection. The cloned Ocrl sequence features a deletion of the downstream portion of exon 19, all of exon 20, and the upstream portion of exon 21 with an in-frame stop codon in the remaining half of exon 19 just upstream of an artificial BglII restriction site. Electroporation of target vector into CCE ES cells (origin: 129S8-Gpi1c), yielding 6 correctly targeted clones out of 500 geneticin-resistant colonies (verified by Southern blot). Two of the 6 correctly targeted clones were injected into C57BL/6 blastocysts to generate 3 and 6 male chimeras, respectively. One of these males produced two offspring carrying the knockout allele at a low frequency of <1% of all pups, one of which was a heterozygous female used to establish the colony on a 129Sv/J and C57BL/6J mixed background.

  2. Inpp5b-floxed mice:
    Genomic fragments containing the Inpp5b gene were cloned from a 129S6 mouse genomic library. To construct a conditional targeting vector, a 1.8-kb Neo cassette flanked from its end by a loxP site from pPNT-loxP was cloned into a SpeI site in an intron downstream of Inpp5b exon 15. A second loxP site was cloned into an NsiI site in an intron upstream of Inpp5b exon 15, disrupting the site. The integrity of both loxP sites was verified by sequencing. The TK cassette from pPNT-loxP was cloned into a downstream SpeI site. A unique NotI site 5' of the homologous sequence was used to linearize the targeting vector before electroporation into TC-1 ES cells. Transfected TC-1 ES cells were selected in G418, and resistant colonies screened by Southern blotting. External 0.3-kb SpeI/BamHI (probe B) and internal 1.0-kb EcoRI (probe A) fragments were used as probes to verify correct targeting and the presence of the loxP site, observed by NcoI and NsiI digests of the tail DNA. Two ES cell clones were injected into C57BL/6J blastocysts. Two male chimeras transmitted through the germline and were used to generate homozygous 129S6.Inpp5bflox/flox animals.

  3. Tg(INPP5B)CNbm: Seven founder mice expressing and transmitting INPP5B were generated by pronuclear injection of a bacterial artificial chromosome containing the human INPP5B gene (BAC RP11-431J04) into fertilized FVB/N oocytes. Three of these lines of mice were bred with Inpp5bflox/flox mice (described above in section 2) and subsequently with Ocrl-deficient mice (described above in section 1) to generate live-born Ocrl-/-;Inpp5bflox/flox females and Ocrl-/Y;Inpp5bflox/flox males that were either homozygous or hemizygous for the INPP5B transgenic allele. These Lowe Syndrome mice were backcrossed to C57BL/6J mice and maintained via sibling intercrosses between Ocrl+/-;Inpp5bflox/flox;INPP5BTg/Tg females and Ocrl-/Y;Inpp5bflox/flox;INPP5BTg/Tg males.
Suggested Control Mice
Siblings that are homozygous for Ocrl+/+ (WT), Inpp5bflox/flox (floxed), and INPP5BTg/Tg (KI).
MMRRC Genetic QC Summary
The MMRRC Centers have developed a genetic QC pipeline using MiniMUGA array genotyping to provide additional information on strain backgrounds for MMRRC congenic and inbred strains. For more information on when data may be available, or to request genotyping for a strain of interest, please contact mmrrc@ucdavis.edu. Older strains may not have this information.
  • Cell Biology
  • Internal/Organ
  • Metabolism
  • Models for Human Disease
Donor
Robert L. Nussbaum, M.D., University of California, San Francisco.
Marisa W. Medina, Ph.D., Childrens Hospital Oakland Research Institute.
Primary Reference

Festa BP, Berquez M, Gassama A, Amrein I, Ismail HM, Samardzija M, Staiano L, Luciani A, Grimm C, Nussbaum RL, De Matteis MA, Dorchies OM, Scapozza L, Wolfer DP, Devuyst O. OCRL Deficiency Impairs Endolysosomal Function in a Humanized Mouse Model for Lowe Syndrome and Dent Disease. Hum Mol Genet. 2018 Dec 26. doi: 10.1093/hmg/ddy449. [Epub ahead of print] (Medline PMID: 30590522)

Bothwell SP, Chan E, Bernardini IM, Kuo YM, Gahl WA, Nussbaum RL. Mouse model for Lowe syndrome/Dent Disease 2 renal tubulopathy. J Am Soc Nephrol. 2011Mar;22(3):443-8. doi: 10.1681/ASN.2010050565. Epub 2010 Dec 23. (Medline PMID: 21183592)

Jänne PA, Suchy SF, Bernard D, MacDonald M, Crawley J, Grinberg A,Wynshaw-Boris A, Westphal H, Nussbaum RL. Functional overlap between murineInpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 doesnot cause Lowe syndrome in mice. J Clin Invest. 1998 May 15;101(10):2042-53.(Medline PMID: 9593760)

Hellsten E, Evans JP, Bernard DJ, Jänne PA, Nussbaum RL. Disrupted spermfunction and fertilin beta processing in mice deficient in the inositolpolyphosphate 5-phosphatase Inpp5b. Dev Biol. 2001 Dec 15;240(2):641-53. (Medline PMID: 11784089)

Colony and Husbandry Information

Colony Surveillance Program and Current Health Reports

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email mmrrc@ucdavis.edu.
Coat Color
Black, white, and agouti.
Eye
Mice with black and agouti coats have black eyes, while mice with white coats have red/pink eyes.
Other
Per Co-donor, Dr. Medina: "These mice were originally generated and studied in the now-closed Nussbaum Lab at UCSF. The initial attempts to create a mouse model for Lowe oculocerebrorenal syndrome were met with great difficulty since at least 1998 or prior, and we believe the loss of this mouse line would be detrimental to the scientific community. Additionally, since the OCRL gene encodes a type II phosphatidylinositol bisphosphate 5-phosphatase, Ocrl enzyme deficiency in these mice is a great model for the study of phosphoinositides and their regulatory effects on lipid transport. We have not published data about this mouse line, so we have not received any requests for this mouse [...] the [JAX] Genetic Resource Committee felt quite strongly that this mouse line should be made available to the greater scientific community"
MMRRC Breeding System
Sib-mating
Generation
Unknown - occurred prior to transfer from the Nussbaum Lab to the Medina Lab. SNP genome scanning analysis of ~150 SNPs from JAX services determined the mice are ~81% C57BL/6J as of December 2016.
Overall Breeding Performance
Good
NOTE: "Hemizygote" as used here refers to males carrying a mutation on the X Chromosome or mice of either sex carrying an inserted transgene with no homologous allele on the other chromosome.
Viability and Fertility: Female Male Comments
Homozygotes are viable: Yes Yes
Homozygotes are fertile: Reduced N/A
Hetero/Hemizygotes are fertile: Yes Reduced
Age Reproductive Decline: 8 to 12 months Undetermined
Bred to Homozygosity
Yes
Average litter size
7-9
Recommended wean age
May require up to 4 weeks for particularly small pups, but we have been weaning them at 21-24 days without issues.
Average Pups Weaned
4-6

Order Request Information

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Cryopreserved material may be available upon request, please inquire to mmrrc@ucdavis.edu for more information.

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # Description Distribution Fee / Unit (US $)
*Shipping & Handling not included*
Units Notes
050927-UCD-EMBRYO Cryo-preserved embryos $1,038.00 / $1,545.65
Non-Profit / For-Profit
Aliquot Approximate quantity2 : 20-40 embryos / aliquot
050927-UCD-SPERM Cryo-preserved spermatozoa $546.25 / $869.88
Non-Profit / For-Profit
Aliquot Approximate quantity3
050927-UCD-RESUS Litter recovered from cryo-archive $4,044.00 / $7,650.23
Non-Profit / For-Profit
Litter Recovered litter4; additional fees for any special requests.

1 The distribution fee covers the expense of rederiving mice from a live mouse; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

3 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

4 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.