Practice question

Familial hypercholesterolemia prototypical autosomal co-dominant hyperlipidemia illustrating receptor-mediated endocytosis studied Brown Goldstein Nobel 1985 award. Clinical features elevated plasma LDL two to three fold heterozygotes six fold homozygotes tendon xanthomas cholesterol deposition xanthelasma corneal arcus premature atherosclerotic coronary disease often teens homozygotes severe. Molecular lesion mutations LDLR gene locus 19p13.2 encoding 860 aa receptor 18 exons. Over 2000 pathogenic variants classified five classes: class 1 null no synthesis, class 2 transport defective ER retention, class 3 binding defective LA repeat, class 4 internalization defective NPXY tail or ARH adaptor, class 5 recycling defective. Heterozygote prevalence 1 in 220, homozygote 1 in 300k to million. Pathway failure prevents hepatic uptake increasing circulating LDL cholesterol. Transferrin receptor mutations affect iron metabolism anemia, Hsp70 influences folding general, dynamin impairs vesicle scission not cholesterol specifically. Identification LDLR clarified endocytic regulation feedback via SREBP controlling HMG-CoA reductase and PCSK9 therapeutic target evolocumab relevant cardiology metabolism and genetics and personalized medicine.