International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G6 Dosage Dependent PITX2 Expression in a Mouse Model of Rieger Syndrome

D. M. Martin*, P. J. Gage§, H. Suh¶, P. Eswara§, K. S. O 'Shea†, S. A. Camper§. Departments of *Pediatrics, §Human Genetics, †Anatomy Cell Biology, and ¶The Neuroscience Program, The University of Michigan, Ann Arbor, MI 48109

PITX2 is a member of the bicoid family of homeodomain proteins which play a role in determination of laterality and organogenesis. Loss of function mutations in PITX2 are one cause of Rieger syndrome (RGS), a genetically heterogeneous, dominant congential anomaly syndrome characterized by anterior segmental eye defects and tooth anomalies (MIM 180500, 601499). Some RGS patients exhibit short stature, umbilical hernia, and heart malformations. We have generated an allelic series of Pitx2 mutations in mice using the cre-lox recombination system. Heterozygotes for the hypomorphic (intronic Neo insertion) allele and the null (intragenic deletion) allele are viable. Some heterozygotes exhibit abnormalities that mimic RGS including short stature and ocular and dental abnormalities, consistent with the idea that RGS is a haploinsufficiency disorder. Homozygous null mutant mice are embryonic lethal, with externalization of abdominal and thoracic viscera, ectopia cardis, and abnormal pituitary and eye development. The lack of documented homozygous mutations in humans is consistent with the embryonic lethality observed in the mouse model. Hypomorphic mutant mice (Pitx2Neo/Neo) have an intermediate phenotype, exhibiting less severe defects in eye, heart and pituitary development. In homozygotes for either allele, the heart tube undergoes normal, rightward looping and the stomach is positioned normally. In contrast, homozygotes for both alleles exhibit right isomerization of the lungs. Thus, Pitx2 is required for left-right asymmetry of the lungs but not other organs. This allelic series establishes that Pitx2 is required for the development of multiple organs in a dosage-sensitive manner. The phenotypic variability in humans and mice heterozygous for PITX2 mutations suggests an influence of modifying genes. This mouse model for Rieger syndrome provides a mechanism to identify these genes. Also, heart and abdominal wall defects are a consistent finding in Pitx2 homozygous mouse mutants, suggesting that other human congenital anomaly syndromes which include cardiac and abdominal defects may also involve PITX2 mutations.

(Supported by NICHD 30428 and 34283, Glaucoma Research Foundation.)


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