LDL Receptor - Mutations

Mutations

There are 5 broad classes of mutation of the LDL receptor.

• Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).
• Class 2 mutations prevent proper transport to the Golgi body needed for modifications to the receptor.
  • e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
• Class 3 mutations stop the binding of LDL to the receptor.
  • e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
• Class 4 mutations inhibit the internalisation of the receptor-ligand complex.
  • e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; Y residue converted to a C, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
• Class 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface (but all must be newly synthesised).

For a comprehensive list of LDLR variants go to www.ucl.ac.uk/fh Locus specific databases for PCSK9 and LDLRAP1 can also be found via this site.