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How MC4R variants scramble receptor trafficking
Obesity-linked MC4R mutations disrupt plasma-membrane localization, endocytosis and β-arrestin pathways beyond classical cAMP loss-of-function.
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What cellular processes do MC4R mutations disrupt beyond PM levels?
Endocytosis and intracellular trafficking.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
How many rare obesity-associated MC4R variants were characterized?
48 rare variants (MAF <1%).
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
What fraction of obese-cohort MC4R mutations look WT by cAMP?
Up to 25% do not reduce cAMP.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
What receptor behaviors did authors demonstrate for human MC4R?
Homodimerization and agonist-promoted β-arrestin-mediated endocytosis.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
Which β-arrestin primarily drives MC4R endocytosis?
β-arrestin-2.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
What about 19 rare variants previously called non-pathogenic by cAMP?
They impair PM/EE localization or β-arrestin interaction and are reclassified pathogenic LoF.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
What phenotype links to gain-of-function MC4R variants?
Protection from obesity.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
What do many missense MC4R mutations do to surface receptor?
Reduce plasma-membrane expression.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
Why does MC4R matter biologically?
It plays a pivotal role in body-weight regulation.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
How do authors classify trafficking-impaired variants functionally?
As cellular loss-of-function / pathogenic.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified
What clinical implication follows from trafficking assays?
Diagnostic classification should include trafficking/β-arrestin, not cAMP alone.
Source: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation · DOI · quote verified