Disruption of the Clathrin Heavy Chain-Like Gene (CLTCL) Associated with Features of DGS/VCFS: A Balanced (21;22)(p12;q11) Translocation

Abstract

The smallest region of deletion overlap in the patients we have studied defines a DIGeorge syndrome/velocardiofacial syndrome (DGS/VCFS) minimal critical region (MDGCR) of approximately 250 kb within 22q11. A de novo constitutional balanced translocation has been identified within the MDGCR. The patient has some features which have been reported in individuals with DGS/VCFS, including: facial dysmorphia, mental retardation, long slender digits and genital anomalies. We have cloned the breakpoint of his translocation and shown that it interrupts the clathrin heavy chain-like gene (CLTCL) within the MDGCR. The breakpoint of the translocation partner is in a repeated region telomeric to the rDNA cluster on chromosome 21p. Therefore, it is unlikely that the patient's findings are caused by interruption of sequences on 21p. The chromosome 22 breakpoint disrupts the 3' coding region of the CLTCL gene and leads to a truncated transcript, strongly suggesting a role for this gene in the features found in this patient. Further, the patient's partial DGS/VCFS phenotype suggests that additional features of DGS/VCFS may be attributed to other genes in the MDGCR. Thus, haploinsufficiency for more than one gene in the MDGCR may be etiologic for DGS/VCFS.

A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies

“…Cosmid probes specific for chromosome 22 had been isolated from the LL22NCO3 library (Shaikh et al 2000), while BAC clones corresponding to chromosome 8 sequences were selected on the basis of their location from the UCSC database (http://genome.ucsc.edu/) and purchased from BACPAC resources (http://bacpac.chori.org/). All probes used for FISH were labeled by nick translation and applied to metaphase spreads using pre-and posthybridization conditions described previously with minor modifications (Trask 1991;Holmes et al 1997).…”

Clathrin Isoform CHC22, a Component of Neuromuscular and Myotendinous Junctions, Binds Sorting Nexin 5 and Has Increased Expression during Myogenesis and Muscle Regeneration

“…The LCs control CHC17 assembly in the cell and interact with a number of accessory proteins involved in CCV function. The second isoform of clathrin heavy chain, CHC22, was discovered during the human genome project analysis of chromosome 22 (Kedra et al, 1996;Long et al, 1996;Sirotkin et al, 1996;Holmes et al, 1997). CHC22 mRNA was observed at high levels in skeletal muscle, somewhat lower levels in cardiac muscle and testes, and only at low levels in other tissues.…”

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome

“…8,9 The first small region of overlap (SRO1), about 300 Kb in size, was defined by molecular analysis of patients carrying rare rearrangements, including the translocation between chromosomes 2 and 22 (ADU), associated either with DGS or VCFS phenotypes. [10][11][12] The second region, SRO2, was suggested by analysis of the DGS patient G, presenting with a deletion telomeric to SRO1. 13 A third critical region, SRO3, was defined by a patient with a deletion distal to SRO1 and SRO2, 8 overlapping with the deletion described by Kurahashi et al 7 A novel deletion, SRO4, adjacent to but not overlapping SRO3, was observed in a mother and her two daughters presenting the full DGS/VCFS phenotype.…”