Abstract
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
Highlights
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol
We reported that X-linked intellectual disability (XLID) patients carrying a mutation in coiled-coil domain-containing protein 22 (CCDC22) (c.49A4p.T17A) have aberrant copper homeostasis, as serum copper and serum ceruloplasmin levels are increased in these patients[8]
On further clinical analysis of a large XLID family affected with a CCDC22 p.T17A mutation we discovered that these patients have an increase in total plasma cholesterol and LDL cholesterol levels (Table 1 and Supplementary Fig. 1a), exceeding the 95th percentile corrected for age and gender[15,16]
Summary
On further clinical analysis of a large XLID family affected with a CCDC22 p.T17A mutation we discovered that these patients have an increase in total plasma cholesterol and LDL cholesterol levels (Table 1 and Supplementary Fig. 1a), exceeding the 95th percentile corrected for age and gender[15,16]. One of the patients (V-2, 4 years of age) is too young, and plasma cholesterol levels are not informative in this case[17] In another XLID family with a CCDC22 mutation (p.Y557C) 18), we found that the circulating total cholesterol (TC) and LDL cholesterol of the two patients carrying the mutation were above the 95th percentile (Table 1 and Supplementary Fig. 1b) These observations suggest that mutations in the CCC component CCDC22 are causally related to hypercholesterolaemia. The age is indicated at the moment of clinical evaluation
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