Isolation and characterization of genes from the region deleted in velo-cardio-facial syndrome
Sirotkin, Howard Ira
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Velo-cardio-facial syndrome (VCFS) is an autosomal dominant genetic disorder with an estimated frequency of 1/5,000. The most common features of the syndrome are cleft palate, cardiac abnormalities, learning disabilities and a characteristic mild facial dysmorphology. Over 40 additional phenotypes have been associated with the syndrome. VCFS is phenotypically similar to DiGeorge syndrome (DGS) and the two disorders may represent a phenotypic spectrum. Both disorders have been linked to hemizygosity of 22q11. The majority of VCFS patients have interstitial deletions of 22q11 of 3 Mb. Patients with smaller deletions have been observed and the smallest deletion is about 1 Mb. Because of the complexity of the VCFS phenotype, a complete transcription map of the minimally deleted region may be required to elucidate the etiology of the syndrome.;In an effort to isolate the gene(s) responsible for VCFS we have utilized a hybrid selection protocol to recover expressed sequences from three YACs and a small fosmid contig comprising almost 1 Mb of the minimally deleted region. Six human short fragment libraries derived from total fetus (8-9 week abortus), fetal brain, adult brain, testes, thymus and spleen have been used for the selections. Origins of short fragment cDNAs were confirmed by Southern blot hybridizations and PCR. Short fragment cDNAs were then used to probe long insert cDNA libraries to obtain longer clones. Thus far, we have used the selected material to isolate complete cDNAs for three genes and to isolate longer cDNAs for an additional three genes. The complete cDNAs we have identified and characterized include a new catenin family member termed ARV (armadillo repeat gene deleted in VCFS), a muscle clathrin heavy chain gene (CLCD) and a putative transmembrane encoding gene. The muscle specific clathrin gene is of particular interest because many VCFS patients suffer from hypotonia and a role has been suggested for clathrin in sarcomere structure. Four previously cloned genes, catechol-O-methyl-transferase, TUPLE1, IDD (Integral membrane protein deleted in DiGeorge) and HCF which are known to map to 22q11 were also recovered. Thirteen additional ESTs were generated and mapped within 22q11.