Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase.

[primary hyperoxaluria type 1]

Primary Hyperoxaluria Type I (PH 1 ) is a severe rare disorder of metabolism due to inherited mutations on liver peroxisomal alanine :glyoxylate aminotransferase (AGT ), a pyridoxal 5 '-phosphate (PLP )-dependent enzyme whose deficiency causes the deposition of calcium oxalate crystals in the kidneys and urinary tract . PH 1 is an extremely heterogeneous disease and there are more than 150 disease-causing mutations currently known , most of which are missense mutations . Moreover , the molecular mechanisms by which missense mutations lead to AGT deficiency span from structural , functional to subcellular localization defects . Gly 161 is a highly conserved residue whose mutation to Arg , Cys or Ser is associated with PH 1 . Here we investigated the molecular bases of the AGT deficit caused by Gly 161 mutations with expression studies in a mammalian cellular system paired with biochemical analyses on the purified recombinant proteins . Our results show that the mutations of Gly 161 (i ) strongly reduce the expression levels and the intracellular half -life of AGT , and (ii ) make the protein in the apo-form prone to an electrostatically-driven aggregation in the cell cytosol . The coenzyme PLP , by shifting the equilibrium from the apo- to the holo-form , is able to reduce the aggregation propensity of the variants , thus partly decreasing the effect of the mutations . Altogether , these results shed light on the mechanistic details underlying the pathogenicity of Gly 161 variants , thus expanding our knowledge of the enzymatic phenotypes leading to AGT deficiency .

Diseases
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Diseases presenting "inherited mutations on liver peroxisomal alanine:glyoxylate" symptom

primary hyperoxaluria type 1

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