A Molecular Pathway Revealing a Genetic Basis for Human Cardiac and Craniofacial Defects

Abstract

Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified Ufd1, which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human UFD1L gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that removed exons 1 to 3 of UFD1L was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that UFD1L haploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.

Increased corpus callosum volume in children with chromosome 22q11.2 deletion syndrome is associated with neurocognitive deficits and genetic polymorphisms

“…52 A significant increase in the frequency of the A allele of rs5992403 in UFD1L was reported in patients with schizophrenia. 26 In our study, subjects with 22q11DS with the A allele had a larger genu and total CC volume and a lower truncus volume.…”

Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis

“…We isolated mouse or chick embryos at E7.5-E10.5 or stages 5-24, respectively, in PBS and removed the pericardium, followed by fixation in 4% paraformaldehyde/PBS at 4 °C overnight. We carried out whole-mount in situ hybridization as previously described 37 . For section in situ hybridization, we generated [ 35 S]-labeled antisense riboprobes by in vitro transcription and carried out in situ hybridization on mutant and wildtype embryos at E9.0-E12.5 and adult heart, as previously described 30 .…”

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

“…The choice of E9 for our infection protocol was based on supportive literature showing that this day preceded the timetable for proliferation, differentiation and migration of neurons and glia in embryonic neocortex, hippocampus and cerebellum (Susser et al 1999) and initiation of migration of neural crest derived cells to craniofacial structures (Yamagishi et al 1999) and production of Cajal-Retzius cells (D'Arcangelo et al 1997). The timetables for brain development vary based on various regions of the brain and are clearly based on species of interest.…”