Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies.
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.
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Bin
B
Zhang
Jufang
J
Chang
Ming
M
Fu
Jie
J
Huang
Rakesh
R
Kashyap
Ezequiel
E
Salavaggione
Sanjay
S
Jain
Shashikant
S
Kulkarni
Kulkarni
K
Shashikant
Matthew A
MA
Deardorff
Maria L Giovannucci
ML
Uzielli
Dale
D
Dorsett
David C
DC
Beebe
Patrick Y
PY
Jay
Robert O
RO
Heuckeroth
Ian
I
Krantz
Jeffrey
J
Milbrandt
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D003635:De Lange Syndrome / Q000196:embryology* / Q000235:genetics*; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D017931:DNA Primers; D004268:DNA-Binding Proteins; C118660:PDS5B protein, human; C524054:PDS5B protein, mouse; D014157:Transcription Factors