Variant in C-terminal region of intestinal alkaline phosphatase associated with benign familial hyperphosphatasaemia.

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.