Isolation of a gene encoding an integral membrane protein from the vicinity of a balanced translocation breakpoint associated with DiGeorge syndrome

Abstract

Deletions within 22q11 have been associated with a wide variety of birth defects embraced by the acronym CATCH22 and including the DiGeorge syndrome, Shprintzen syndrome (velocardiofacial syndrome) and congenital heart disease. It is not known how many genes contribute to this phenotype. Previous studies have shown that a balanced translocation disrupts sequences within the shortest region of deletion overlap for DiGeorge syndrome. A P1 clone was isolated which spans this breakpoint and used to isolate a cDNA encoding a transmembrane protein expressed in a wide variety of tissues. This gene (called IDD) is not disrupted by the translocation, but maps within 10 kb of the breakpoint. Mutation analysis of five affected cases with no previously identified chromosome 22 deletion was negative, but a potential protein polymorphism was discovered. No deletions or rearrangements were detected in these patients following analysis with markers closely flanking the breakpoint, data which emphasize that large (i.e. over 1 Mb) interstitial deletions are the rule in DiGeorge syndrome. The proximity of IDD to the balanced translocation breakpoint and its position within the shortest region of deletion overlap indicate that this gene may have a role, along with other genes, in the CATCH22 haploinsufficiency syndromes.

Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization

“…Mouse probes for Arvcf and Idd genes were prepared from partial cDNA clones isolated by screening at low stringency a mouse newborn brain cDNA library (Stratagene). Sequencing confirmed their similarity to ARVCF and IDD͞ DGCR2, respectively (20)(21)(22). Arvcf (1.8-kb EcoRI fragment) and Idd (1.3-kb BamHI fragment) probes were obtained by digestion of plasmids mp120b and mIdd2.3, respectively (BSJ and AP, unpublished data).…”

Recent advances in the understanding of genetic causes of congenital heart defects

“…Breakpoint mapping of deletions and unbalanced translocations defined a minimal critical region of 250 kb (21,(35)(36)(37). Mutation analyses of genes within this critical region in DGS/VCFS patients without 22q11 deletions have been negative (38)(39)(40). Moreover, DGS/VCFS patients with non-overlapping deletions within the 3-Mb common deletion region as well as one with a deletion telomeric to that region have been identified (41)(42)(43).…”

Direct Selection of Conserved cDNAs from the DiGeorge Critical Region: Isolation of a Novel CDC45-Like Gene

“…Comparative mapping between human 22q11 and MMU16 is well delineated (Botta et al 1997;Galili et al 1997), and, in another model organism, the Japanese pufferfish, Fugu rubripes (Brenner et al 1993), genomic clones containing DGCR transcripts such as IDD Wadey et al 1995), HIRA (Halford et al 1993), and ES2 (Rizzu et al 1996) have been isolated (Taylor 1997). In a further extension of the direct selection technique, we used these Fugu rubripes genomic clones to select highly conserved and developmentally expressed murine cDNAs.…”