Failure of endocytic flux in Donnai-Barrow syndrome caused by LRP2 p.C1400R

The *LRP2* p.C1400R missense variant disrupts endocytic recycling flux at endosomal pH despite normal protein expression and localization

Urinary proteomics of 9 Donnai-Barrow syndrome (DBS) patients revealed that the profile of the patient carrying LRP2 p.C1400R was indistinguishable from those with classical loss-of-function variants. A CRISPR mouse model demonstrated that the mutant protein is expressed and correctly localized to the proximal tubule apical membrane, but endocytosis is impaired by a global disruption of endocytic recycling flux. Structural modeling suggests the substitution introduces steric clashes at endosomal pH, disrupting receptor recycling.

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This paper offers a lesson on missense variants that are functionally loss-of-function despite normal expression: LRP2 p.C1400R acts by disrupting endocytic recycling flux, a pH-dependent mechanism novel for this gene. Implications for other renal endocytosis disorders are foreseeable.