title: Standardized, systemic phenotypic analysis of Slc12a1I299F mutant mice.
abstract: BACKGROUND
  Type I Bartter syndrome is a recessive human nephropathy caused by loss-of-function mutations in the SLC12A1 gene coding for the Na+-K+-2Cl- cotransporter NKCC2. We recently established the mutant mouse line Slc12a1I299F exhibiting kidney defects highly similar to the late-onset manifestation of this hereditary human disease. Besides the kidney defects, low blood pressure and osteopenia were revealed in the homozygous mutant mice which were also described in humans. Beside its strong expression in the kidney, NKCC2 has been also shown to be expressed in other tissues in rodents i.e. the gastrointestinal tract, pancreatic beta cells, and specific compartments of the ear, nasal tissue and eye.
  
  
  RESULTS
  To examine if, besides kidney defects, further organ systems and/or metabolic pathways are affected by the Slc12a1I299F mutation as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the mutant mouse line Slc12a1I299F in the German Mouse Clinic. Slc12a1I299F homozygous mutant mice and Slc12a1I299F heterozygous mutant littermates as controls were tested at the age of 4-6 months. Beside the already published changes in blood pressure and bone metabolism, a significantly lower body weight and fat content were found as new phenotypes for Slc12a1I299F homozygous mutant mice. Small additional effects included a mild erythropenic anemia in homozygous mutant males as well as a slight hyperalgesia in homozygous mutant females. For other functions, such as immunology, lung function and neurology, no distinct alterations were observed.
  
  
  CONCLUSIONS
  In this systemic analysis no clear primary effects of the Slc12a1I299F mutation appeared for the organs other than the kidneys where Slc12a1 expression has been described. On the other hand, long-term effects additional and/or secondary to the kidney lesions might also appear in humans harboring SLC12A1 mutations.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Ines
authors.initials: I
authors.lastname: Bolle
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Claudia
authors.initials: C
authors.lastname: Dalke
authors.forename: Ralf
authors.initials: R
authors.lastname: Elvert
authors.forename: Jack
authors.initials: J
authors.lastname: Favor
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Boris
authors.initials: B
authors.lastname: Ivandic
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Kalaydjiev
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Ildikó
authors.initials: I
authors.lastname: Rácz
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewe
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabe de Angelis
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D005260:Female; D006720:Homozygote; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D064466:Solute Carrier Family 12, Member 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C578715:Slc12a1 protein, mouse; D064466:Solute Carrier Family 12, Member 1
references.citation: J Hypertens. 2011 Mar;29(3):475-83
references.pmid: 21157372
references.citation: J Am Soc Nephrol. 2007 Feb;18(2):440-8
references.pmid: 17215439
references.citation: Am J Physiol Renal Physiol. 2007 May;292(5):F1560-7
references.pmid: 17264314
references.citation: J Am Soc Nephrol. 2002 Mar;13(3):604-610
references.pmid: 11856763
references.citation: Methods Mol Biol. 2009;530:463-509
references.pmid: 19266331
references.citation: Am J Physiol Renal Physiol. 2008 Oct;295(4):F859-66
references.pmid: 18495801
references.citation: Nat Genet. 1996 Jun;13(2):183-8
references.pmid: 8640224
references.citation: Steroids. 2010 Nov;75(11):760-5
references.pmid: 20580730
references.citation: Am J Physiol Renal Physiol. 2010 Jun;298(6):F1405-15
references.pmid: 20219826
references.citation: Am J Physiol Renal Physiol. 2011 Apr;300(4):F840-7
references.pmid: 21209010
references.citation: Neurogastroenterol Motil. 2009 Oct;21(10):1068-e89
references.pmid: 19460103
references.citation: J Am Soc Nephrol. 2006 Aug;17(8):2136-42
references.pmid: 16807401
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5434-9
references.pmid: 10779555
references.citation: Korean J Ophthalmol. 2012 Jun;26(3):203-11
references.pmid: 22670078
references.citation: Lab Anim. 2002 Jan;36(1):20-42
references.pmid: 11831737
references.citation: Pflugers Arch. 2014 Jan;466(1):91-105
references.pmid: 24097229
references.citation: J Physiol. 2007 Sep 15;583(Pt 3):1005-20
references.pmid: 17656441
references.citation: Curr Opin Nephrol Hypertens. 2014 Jan;23(1):1-8
references.pmid: 24253496
references.citation: Am J Physiol Renal Physiol. 2011 Dec;301(6):F1143-59
references.pmid: 21900458
references.citation: Biochem Biophys Res Commun. 2007 Dec 28;364(4):913-7
references.pmid: 18273442
references.citation: Nat Genet. 2008 May;40(5):592-599
references.pmid: 18391953
references.citation: Pediatr Nephrol. 2009 Feb;24(2):415-8
references.pmid: 18830715
references.citation: Physiol Rev. 2005 Apr;85(2):423-93
references.pmid: 15788703
references.citation: J Am Soc Nephrol. 2006 Aug;17(8):2143-52
references.pmid: 16807402
references.citation: Nat Genet. 2000 Aug;25(4):444-7
references.pmid: 10932192
references.citation: Pediatr Nephrol. 2005 Feb;20(2):190-6
references.pmid: 15625618
references.citation: Mamm Genome. 2012 Oct;23(9-10):611-22
references.pmid: 22926221
references.citation: Cell Physiol Biochem. 2012;30(1):95-112
references.pmid: 22759959
references.citation: Methods. 2011 Feb;53(2):120-35
references.pmid: 20708688