Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion 
proteins, is characterized by multisystem developmental abnormalities. PDS5, a 
cohesion protein, is important for proper chromosome segregation in lower 
organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant 
mice have developmental abnormalities resembling CdLS; however the role of Pds5A 
in mammals and the association of PDS5 proteins with CdLS are unknown. To 
delineate genetic interactions between Pds5A and Pds5B and explore mechanisms 
underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, 
these mice exhibit multiple abnormalities that were previously observed in 
Pds5B-deficient mice, including cleft palate, skeletal patterning defects, 
growth retardation, congenital heart defects and delayed migration of enteric 
neuron precursors. They also frequently display renal agenesis, an abnormality 
not observed in Pds5B(-/-) mice. While Pds5A(-/-) and Pds5B(-/-) mice die at 
birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most 
likely of heart failure, indicating that total Pds5 gene dosage is critical for 
normal development. In addition, characterization of these compound 
homozygous-heterozygous mice revealed a severe abnormality in lens formation 
that does not occur in either Pds5A(-/-) or Pds5B(-/-) mice. We further 
identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding 
domain in a familial case of CdLS, in which affected individuals also develop 
megacolon. This study shows that PDS5A and PDS5B functions other than those 
involving chromosomal dynamics are important for normal development, highlights 
the sensitivity of key developmental processes on PDS5 signaling, and provides 
mechanistic insights into how PDS5 mutations may lead to CdLS.