title: The role of a single formin isoform in the limb and renal phenotypes of limb deformity.
abstract: BACKGROUND
  Mutations of the murine limb deformity (ld) locus are responsible for a pleiotropic phenotype of completely penetrant limb malformations and incompletely penetrant renal agenesis and/or dysgenesis. The ld locus encodes a complex family of mRNA and protein isoforms.
  
  
  METHODS
  To examine the role of one of the more prominent of these isoforms, isoform IV, we specifically eliminated it by gene targeting.
  
  
  RESULTS
  Unlike other mutant ld mice, homozygous mice bearing this isoform IV disruption display incompletely penetrant renal agenesis, but have perfectly normal limbs. Whole mount in situ hybridization demonstrated that this targeted disruption was specific for isoform IV and did not interfere with the expression of other ld isoforms. The isoform IV-disrupted allele of ld does not complement the renal agenesis phenotype of other ld alleles, in a manner consistent with its penetrance, and like the isoform IV-deficient mice, these compound heterozygotes have normal limbs. Sequence analysis of formin isoform IV in other ld mutant alleles did not detect any amino acid changes relative to the strain of origin of the mutant allele.
  
  
  CONCLUSIONS
  Thus, the disruption of isoform IV is sufficient for the renal agenesis phenotype, but not the limb phenotype of ld mutant mice. Structural mutations in this isoform are only one of several genetic mechanisms leading to the renal phenotype, since amino acid changes in this isoform were not detected. These results demonstrate that this gene is limb deformity, and that variable isoform expression may play a role in generating the pleiotropic ld phenotype.
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: G
authors.initials: G
authors.lastname: Ryan
authors.forename: C X
authors.initials: CX
authors.lastname: Deng
authors.forename: D C
authors.initials: DC
authors.lastname: Chan
authors.forename: L
authors.initials: L
authors.lastname: Jackson-Grusby
authors.forename: D
authors.initials: D
authors.lastname: Larson
authors.forename: J H
authors.initials: JH
authors.lastname: Dunmore
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000235:genetics; D005326:Fetal Proteins / Q000235:genetics*; D000080865:Formins; D018390:Gene Targeting; D017403:In Situ Hybridization; D007668:Kidney / Q000002:abnormalities*; D017880:Limb Deformities, Congenital; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000302:isolation & purification; D017422:Sequence Analysis, DNA
chemical_list: D018076:DNA, Complementary; D005326:Fetal Proteins; D000080865:Formins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger