Background A genetic diagnosis has been rarely performed in benign familial hyperphosphatasaemia, and molecular mechanism largely remains unclear.

Objectives We encountered a case with benign familial hyperphosphatasaemia of intestinal alkaline phosphatase (IAP). To elucidate the molecular mechanism, we performed ALPI gene sequencing and in vitro protein expression analysis.

Methods ALPI gene was sequenced by long-range PCR and massively parallel sequencing. The soluble and membrane-bound ALP activities of the cultured cell line, transfected with the wild-type or variant-type ALPI gene were analysed by a glycosylphosphatidylinositol (GPI)-cleaving assay.

Results We identified a deletion–insertion variant in the C-terminal end of the ALPI gene. This variant causes the attenuation of the hydrophobicity in GPI-anchor signal of IAP. An in vitro GPI-cleaving assay demonstrated that the membrane-bound IAP was greatly decreased, whereas the soluble IAP was increased, in the variant IAP.

Conclusions The C-terminal variant in ALPI causes the benign familial hyperphosphatasaemia of IAP by the attenuation of the membrane-binding capability.