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.
Bashiardes
Stavros
S
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
Veile
Rose
R
Allen
Missy
M
Wise
Carol A
CA
Dobbs
Mathew
M
Morcuende
Jose A
JA
Szappanos
Lazlos
L
Herring
John A
JA
Bowcock
Anne M
AM
Lovett
Michael
M
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D007446:Chromosome Inversion; D020090:Chromosome Segregation; D022202:Chromosomes, Artificial, Bacterial; D002898:Chromosomes, Human, Pair 8; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D020161:Physical Chromosome Mapping; D012600:Scoliosis / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C432243:SNTG1 protein, human