An isoform specific disruption of the murine limb deformity locus distinguishes the renal and limb phenotypes

Journal Article · Thu Sep 01 04:00:00 EDT 1994 · American Journal of Human Genetics

OSTI ID:133807

Wynshaw-Boris, A; Deng, C; Chan, D; Leder, P ^[1]

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1. Harvard Medical School, Boston, MA (United States)

The limb deformity locus (ld) on mouse chromosome 2 is required for the normal development of the limbs and kidney. Five recessive ld mutants have been described, all of which result in shortened limbs, oligosyndactyly, fusion of the long bones of the upper and lower limbs, and renal agenesis. The limb phenotype is completely penetrant in all animals homozygous for any of the mutant alleles, but there is incomplete penetrance and variable expressivity of the kidney abnormalities in homozygotes. A candidate ld gene has been cloned in this laboratory, using a transgene insertion as a molecular tag. A complex pattern of mRNA isoform products are produced by differential promoter utilization, alternative splicing, and differential polyadenylation, and these potentially code for a family of proteins, the formins. One isoform (IV) has a spatial and temporal pattern of expression consistent with a role for this isoform in the mutant phenotype. To begin to dissect the role of individual isoforms in limb and kidney development, a null mutation of isoform IV was generated by gene targeting in embryonic stem cells and established in mice. No protein was detectable in homozygous mutant mice (-/-) by Western analysis. -/- mice had no detectable limb abnormality. However, 6% of homozygous mutants had unilateral or bilateral renal agenesis. These results demonstrate that the candidate ld gene is responsible for the mutant phenotype. The disruption of isoform IV is sufficient for the kidney, but not the limb abnormalities, suggesting molecular differences between the action of specific isoforms in these tissues.

• OSTI ID: 133807
• Report Number(s): CONF-941009--
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
CHROMOSOMES
CONGENITAL MALFORMATIONS
DNA-CLONING
GENE MUTATIONS
GENES
KIDNEYS
LIMBS
MESSENGER-RNA
MICE
ONTOGENESIS
PHENOTYPE
TISSUE DISTRIBUTION
UROGENITAL SYSTEM DISEASES