DiGeorge syndrome: complex pathogenesis? Maybe, maybe not.

For almost a decade, human geneticists have searched for the gene(s) responsible for the developmental defects associated with an interstitial deletion of chromosome 22 (del22q11). These defects mainly affect the cardiovascular system, thymus and parathyroids. So far, the search for the causative gene(s) has been unsuccessful, and the frustration that derives from the lack of a common region of deletion overlap (see Fig. 1 of Novelli et al.1xIndividual haploinsufficient loci and the complex phenotype of the DiGeorge syndrome. Novelli, G. et al. Mol. Med. Today. 2000; 6: 10–11Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References1) has sometimes driven investigators to propose complex (and even exotic) models. Whatever the reason by which non-overlapping deletions cause similar abnormalities, one thing is clear: the del22q11 region harbors one or more dosage-sensitive genes that are important for embryonic development. The heart, thymic and parathyroid (and perhaps craniofacial) abnormalities of DiGeorge syndrome (which is mainly caused by del22q11) have been attributed to a single problem: impaired development of the pharyngeal arches and arch artery derivatives2xDiGeorge’s or the III–IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis. Robinson, H.B. Jr. Perspect. Pediatr. Pathol. 1975; 2: 173–206PubMedSee all References, 3xCardiovascular anomalies in DiGeorge syndrome and importance of neural crest as a possible pathogenetic factor. Van Mierop, L.H. and Kutsche, L.M. Am. J. Cardiol. 1986; 58: 133–137Abstract | Full Text PDF | PubMed | Scopus (224)See all References, 4xThe developmental field concept in pediatric pathology – especially with respect to fibular a/hypoplasia and the DiGeorge anomaly. Opitz, J.M. and Lewin, S.O. Birth Defects Orig. Artic. Ser. 1987; 23: 277–292PubMedSee all References. Although there is still no evidence that this is the case, this unifying view is reasonable and transforms the complex del22q11-associated phenotype into a conceptually ‘simple’ developmental problem.By chance or by design, some light, and a lot of excitement, is coming from mouse genetics. Two reports this year have stirred debate in the literature5xA molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Yamagishi, H. et al. Science. 1999; 283: 1158–1161Crossref | PubMed | Scopus (214)See all References, 6xCongenital heart disease in mice deficient for the DiGeorge syndrome region. Lindsay, E.A. et al. Nature. 1999; 401: 379–383PubMedSee all References, and Novelli and colleagues address both in their letter1xIndividual haploinsufficient loci and the complex phenotype of the DiGeorge syndrome. Novelli, G. et al. Mol. Med. Today. 2000; 6: 10–11Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References1. Our Df1/+ mice (a model of del22q11) recapitulate most of the del22q11-associated cardiovascular defects. However, in the sample of mutants so far analysed, no thymic, parathyroid or gross craniofacial abnormalities were noted.A mouse mutant phenotype should always be interpreted with caution. In the case of Df1/+ mice, the phenotypic effects of the deletion were analysed in a hybrid genetic background, and it is likely that in inbred mice the abnormal phenotype will be more extensive. Furthermore, the heterozygous mutation of genes that are haploinsufficient in humans often has little or no phenotypic effect in mice. Hence, it should not be surprising that the heterozygous deletion of the del22q11 region in mice results in a less extensive phenotype than that of many human patients. We consider that the difference between the Df1/+ phenotype and severely affected del22q11 patients is likely to be simply quantitative, because the embryological defect in mice is found exactly where it was expected to be, in the pharyngeal arches. We hypothesize that the gene (or genes) that are haploinsufficient in the Df1/+ mice is (or are) responsible for the main del22q11 phenotype (as defined above). The suggestion of Dr Novelli, that the differences between Df1/+ mice and human patients could be due to transcripts that are not evolutionarily conserved in mice, seems far less likely. There is no evidence in the literature to suggest that human genes that are not conserved in mice regulate vital developmental processes.The gene Ufd1l , which is highly conserved, is included in the Df1 and del22q11 deletions and was proposed as a major candidate for the del22q11 phenotype5xA molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Yamagishi, H. et al. Science. 1999; 283: 1158–1161Crossref | PubMed | Scopus (214)See all References5. However, deletion of this gene alone is insufficient to generate the cardiovascular defects observed in Df1/+ mice6xCongenital heart disease in mice deficient for the DiGeorge syndrome region. Lindsay, E.A. et al. Nature. 1999; 401: 379–383PubMedSee all References6. Whether or not deletion of this gene is necessary for those defects to develop is an important question that remains unanswered. It is intriguing that Ufd1l is expressed at the time and in the region where the Df1/+ embryological defect occurs. The function of the Ufd1l gene is unknown, but we do know that this gene is essential in very early mouse embryogenesis, much earlier than the time when the organs and structures affected by del22q11 develop (Ref.6xCongenital heart disease in mice deficient for the DiGeorge syndrome region. Lindsay, E.A. et al. Nature. 1999; 401: 379–383PubMedSee all ReferencesRef.6 and our unpublished data). It is likely that Ufd1l is required for vital cellular functions.The apparent consistency of the human disease phenotype, despite the inconsistency of the deletions, suggests that haploinsufficiency of one or maybe two genes (that interfere with the same developmental pathway) is the basis of the abnormal phenotype. It is not unreasonable to think that cells deleted for one copy of Ufd1l might be more sensitive to other genetic insults, like deletion of another critical gene within Df1. This could be especially true for cells of the pharyngeal arches, which normally express high levels of Ufd1l .It is important that we clarify the mechanisms behind the defects in del22q11-related mouse models. Then we will be much better equipped to address the complicated issues behind the human disease. So, let the excitement continue…surely more mice are coming!