Direct genomic selection.
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Biotinylation↗
Biomedical subjects
Rose Veile
Publications and source records attributed to Rose Veile.
SNTG1, the gene encoding gamma1-syntrophin: a candidate gene for idiopathic scoliosis.
Idiopathic scoliosis (IS) affects approximately 2%-3% of the population and has a heritable component. The genetics of this disorder are complex. Here, we describe a family in which a pericentric inversion of chromosome 8 co-segregates with IS. We have used fluorescence in situ hybridization to identify cloned DNAs that span the breakpoints on the two arms of the chromosome. We have identified a bacterial artificial chromosome (BAC) of 150 kb that crosses the q-arm breakpoint and a BAC of 120 kb that crosses the p-arm breakpoint. The complete genomic DNA sequence of these BACs has been analyzed to identify candidate genes and to localize further the precise breakpoints. This has revealed that the p-arm break does not interrupt any known gene and occurs in a region of highly repetitive sequence elements. On the q-arm, the break occurs between exons 10 and 11 of the gamma-1 syntrophin (SNTG1) gene. Syntrophins are a group of cytoplasmic peripheral membrane proteins that associate directly with dystrophin, the Duchenne muscular dystrophy gene; gamma1-syntrophin has been shown to be a neuronal cell-specific protein. Mutational analysis of SNTG1 exons in 152 sporadic IS patients has revealed a 6-bp deletion in exon 10 of SNTG1 in one patient and a 2-bp insertion/deletion mutation occurring in a polypyrimidine tract of intronic sequence 20 bases upstream of the SNTG1 exon 5 splice site in two patients. These changes were not seen in a screen of 480 control chromosomes. Genomic DNAs from seven affected individuals within the family of a patient carrying the 6-bp deletion were typed to determine whether the alteration co-segregated with IS. The deletion was only observed in five out of these seven individuals. Thus, although genetic heterogeneity or multiple alleles cannot be ruled out, the 6-bp deletion does not consistently co-segregate with the disease in this family.
Adaptor Proteins, Signal Transducing↗
Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder.
PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne, OMIM #604416) and familial recurrent arthritis (FRA) are rare inherited disorders of early onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. We recently localized the genes for PAPA syndrome and FRA to chromosome 15q and suggested that they are the same disorder. We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1 (CD2BP1; GenBank accession no XM 044569) gene in the two reported families with this disorder. E250Q or A230T amino acid substitutions occur within a domain highly homologous to yeast cleavage furrow-associated protein CDC15. CD2BP1 and its murine ortholog, proline-serine-threonine phosphatase interacting protein (PSTPIP1), are adaptor proteins known to interact with PEST-type protein tyrosine phosphatases (PTP). Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins. Previous evidence supports the integral role of CD2BP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. We hypothesize that the disease-causing mutations that we have identified compromise physiologic signaling necessary for the maintenance of proper inflammatory response. Accordingly we suggest classification of PAPA syndrome as an autoinflammatory disease. This CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease.
Acne Vulgaris↗
Positional cloning strategies for idiopathic scoliosis.
AIM: Idiopathic scoliosis (IS) affects approximately 1-2% of the population and has a heritable component. It is clear that in general IS displays the features of a complex genetic disorder; however families displaying a Mendelian inheritance pattern have been described. Our aim is to identify families segregating rare, highly penetrant loci. In the case described here the disorder appears to cosegregate with a chromosomal rearrangement. METHODS AND MATERIALS: We have studied a family in which a pericentric inversion of chromosome 8 appears to cosegregate with idiopathic scoliosis in three generations. We have used fluorescent in situ hybridization (FISH) to identify cloned DNAs that span the breakpoints on the two arms of the chromosome. These clones allow the recovery of sequence information from the breakpoint region and identification of candidate genes. RESULTS: We have identified a YAC of 1190kb that spans the p arm breakpoint and from this a cosmid of 35kb that also identifies the break. We have derived DNA sequence information on this region. We have identified a BAC of 150kb that crosses the q arm breakpoint. The complete genomic DNA sequence of this BAC is being analyzed to identify candidate genes and to further localize the precise breakpoint. CONCLUSION: We have sublocalized within two small genomic regions the position of a possible locus for idiopathic scoliosis.
Adolescent↗