Secretin gene structure, chromosome localization and mutation analysis on autism. T. Yamagata1, S. Aradhya1, M. Mori2, M.Y. Momoi2, D.L. Nelson1. 1) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) Department of Pediatrics, Jichi Medical School, Tochigi, Japan.
Secretin is a 27-amino acid gastrointestinal hormone. The main action of secretin is to stimulate the pancreas to produce pancreatic juice; however, a role for secretin in brain has been proposed. Recently, secretin was reported to improve some symptoms of autism in some patients. Therefore, we cloned human secretin gene, identified its position in the genome and analyzed the gene for mutations in autistic patients. We designed PCR primers from the sequence of pig secretin and amplified the secretin gene from human genomic DNA. Using this PCR product as a probe, we screened the RPCI-11 BAC library and isolated the clones carrying the secretin gene. The gene is composed of four exons. On the upstream site of the secretin gene, there is a VNTR that ranges from 11 to 14 repeats of a 30 or 31 bp sequence. The secretin gene was mapped between HRAS-1 and DRD4 on 11p15.5, distal to IGF2 - H19 imprinting region first by FISH and later using specific markers in the BAC contig. The promoter region of the secretin gene is not methylated in blood cells. Twenty-five Japanese autism patients were screened by heteroduplex analysis for mutations in the secretin gene. Two patients were found to carry nucleotide substitutions. One mutation was G to C change on the E-box of the promoter and the other was C to T change in exon 3 that altered an amino acid from Pro to Leu. Each patient was heterozygous for their mutation. We screened these mutations in 58 Japanese and 50 Caucasian controls. The mutation in the promoter region was found in two Japanese and none of the Caucasian samples. It is likely to be a Japanese-specific polymorphism. The mutation in exon 3 was not found in the control samples. Family studies revealed that both the normal mother and the unaffected sister of the proband carried this mutation. Although this mutation may lead to autism in this patient, its contribution might involve reduced penetrance or possibly a sex bias. Our results suggest a possible relationship between secretin gene mutations and autism, however, further analyses are required.