Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis.

Deficiency of huntingtin interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a deficiency allele where a floxed transcriptional stop-cassette and a human cDNA were knocked-in to intron 1 of mouse locus. --mediated germline excision of the stop-cassette resulted in expression of HIP1 and rescue of the knockout phenotype. -mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, -mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several knockout tissues identified low phosphocholine (PC) levels and low ) expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, downregulation could lead to the low PC levels. To test if contributes to the deficiency phenotype, we generated knockout mice. Double knockout of and worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More detailed knowledge of how deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.