Early Onset Adrenal Tumour in a Child With Familial Adenomatous Polyposis and APC Mutation at Codon 1309

Abstract

Sucrase-isomaltase (SI) is an enzyme complex with 2 activities, sucrase (SUC) and isomaltase (IM) that is expressed at the small intestine brush-border membrane, where it serves as a catalyst for the cleavage of sugar and starch. A 2006 report identified compound heterozygous mutations (CHM) at V577G (IM) and G1073D (SUC). Cellular studies have documented that V577G (IM) and G1073D (SUC) mutations inhibit exiting from the ER; the SUC mutation blocks its chaperone function for IM. Objective: Test the mode of inheritance in a family with CHM-CSID. Methods: Study of 3 siblings with CSID diagnosed by duodenal enzyme assays and 22 kindred by sucrose breath testing (SBT) and genomic SI sequencing. UL 13C-glucose and 13C-sucrose, (20mg, Isotec, Miamisburg, OH) were given orally. Breath samples were collected for 120 min. Breath 13CO2 enrichments were measured with a infrared spectrophotometer (POCone, Otsuka Electronics, Tokyo, Japan) and expressed as % coefficient of mean 30-90 min sucrose / glucose oxidation (CGO %). Controls were 16 kindred without mutations. DNA was isolated from blood using the Nucleon BACC2 kit (GE Healthcare, Freiburg, Germany) and all exons of SI were amplified by PCR and directly sequenced on an ABI 3730 capillary sequencer (Applied Biosystems, CA). Results: The 3 siblings, father and paternal grandmother had deficient digestion (< 98 CGO %) by SBT. Sequencing of SI revealed polymorphisms at V577G, G1073D, G1476A and I1523M. The G1073D allele was paternal and the remaining maternal polymorphisms. Conclusion: SBT phenotype correlated with sucrase activity and SI genotypes in this CHM-CSID family. The novel maternal mutations G1476A and I1523M of SUC appear to act as dominant negatives suppressing sucrose digestion in the youngest child lacking the familial V577G IM mutation. Characteristics of 3 Siblings with CSID