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Di George Syndrome is a congenital immune disorder characterized by lack of embryonic development (stage in prenatal development between 2-8 weeks inclusive) or underdevelopment of the third and fourth pharyngeal pouches. It is also called thymic aplasia (failure of the thymus to develop naturally), thymic hypoplasia (defective development of tissue), or third and fourth pharyngeal arch or pouch syndrome. The syndrome is often associated with congenital heart defects, abnormalities of the large blood vessels around the heart, failure of the esophageal tube to develop, abnormalities of facial structures, and of hypoparathyroidism (insufficient secretion of the parathyroid glands). In most cases, there is a chromosomal defect on chromosome 22. The similarity between the Hoxa-3 null mutant phenotype and that of humans affected by the Di George Syndrome is remarkable. Hoxa-3 and Hoxb-3 are expressed in the neural tube, in neural crest cells emanating from r5 - r8, and also in the third and fourth branchial arches endoderm and ectoderm. This is because members of the third paralogous group of Hox genes have their anterior limit of expression in the neural tube at the boundary between r4 and r5. (Figure on pp. 100 of Le Douarin)
These malformations are strikingly similar to those recorded in the
congenital human Di George Syndrome in the haploid state (diploid mutants
are lethal). Although the similarity between the Hoxa-3 null mutant
phenotype and that of humans affected by the Di George Syndrome is certainly
remarkable, the Di George Syndrome is autosomal dominant and associated
in certain cases with deletions and translocations involving chromosome
22. The anomalies resulting from Hoxa-3 loss of function are autosomal
recessive and Hoxa-3 maps to chromosome 7. Most patients with the Di
George syndrome have a normal karyotype and may present point mutations
in the Hoxa-3 gene. The similarity of the two
phenotypes suggests that the two genes belong to a common developmental
molecular pathway. |
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