22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development
ABSTRACT We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1Deletion Syndrome (22q11DS). Sonic hedgehog (Shh) and Retinoic Acid (RA) signaling is altered in the brain and heart-clinically significant 22q11DS phenotypic sites-in LgDel mouse embryos, an established 22q11DS model. LgDel embryos treated with cyclopamine, a Shh inhibitor, or carrying mutations in Gli3(Xtj), a Shh signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequencies in control or single mutant embryos. Similarly, RA exposure or genetic loss of RA function via heterozygous mutation of the RA synthetic enzyme Raldh2 induces novel cranial anomalies and enhances cardiovascular phenotypes in LgDel but not other genotypes. These changes are not seen in heterozygous Tbx1 mutant embryos-a 22q11 gene thought to explain much of 22q11DS pathogenesis-in which Shh or RA signaling has been similarly modified. Our results suggest that full dosage of 22q11 genes beyond Tbx1 establish an adaptive range for morphogenetic signaling via Shh and RA. When this adaptive range is constricted by diminished dosage of 22q11 genes, embryos are sensitized to otherwise benign changes in Shh and RA signaling. Such sensitization, in the face of environmental or genetic factors that modify Shh or RA signaling, may explain variability in 22q11DS morphogenetic phenotypes.
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ABSTRACT: Background: Patients with chromosome 22q11.2 deletion syndrome (22q11DS) are at a seven fold increased risk of developing seizures. However, only a fraction of these patients exhibit structural abnormalities such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) that are known to cause seizures and to be associated with 22q11DS. In this study we used a dedicated seizure imaging protocol to look for additional structural abnormalities in these individuals that may explain the elevated risk of seizure disorder in this patient group. Methods: Nineteen consecutive adult subjects with 22q11DS underwent a 3 Tesla MRI with a dedicated high-resolution seizure protocol. Neurological exam was performed in all patients. Genome-wide analysis excluded the presence of other pathogenic microdeletions or duplications. Results: Structural abnormalities were found in 11 of 14 subjects with sufficient image quality. These included three patients with PNH, one of whom had associated PMG. In addition, there was a surprisingly high prevalence of unilateral hippocampal malrotation (HIMAL), observed in 9 of 14 cases (64%). EEG findings showed interictal epileptiform discharges with focal distribution in four patients and generalized discharges in one patient. Conclusion: The results suggest that, in addition to other known structural abnormalities, 22q11DS is associated with HIMAL. It has been suggested that this developmental abnormality of the hippocampus may predispose or otherwise contribute to epileptogenesis. However in this study we observed HIMAL in a large proportion of patients, with and without epilepsy. Therefore, other as yet unknown factors may contribute to the high prevalence of epilepsy in this population.The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 09/2013; 40(5):652-6. DOI:10.1017/S0317167100014876 · 1.60 Impact Factor
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ABSTRACT: We assessed feeding-related developmental anomalies in the LgDel mouse model of Chromosome 22q11 Deletion Syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia - debilitating feeding, swallowing and nutrition difficulties from birth onward - within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX), or vagus (X) cranial nerves (CN) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to that in wild type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and cranial nerve development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.Disease Models and Mechanisms 12/2013; 7(2). DOI:10.1242/dmm.012484 · 5.54 Impact Factor