Associated disorders VLDL receptor

1 associated disorders

1.1 type 1 lissencephaly
1.2 vldlr-associated cerebellar hypoplasia
1.3 atherosclerosis

associated disorders

mutations within vldlr gene lead multitude of disorders of varying severities. these disorders associated cholesterol homeostasis or disorganization of neuron ordering in brain due disruption of reelin pathway. prominent of these diseases type lissencephaly, vldr-associated cerebellar hypoplasia, , atherosclerosis. in contrast causing diseases, vldlr has been identified possible remedy disorders. implementation of vldlr liver may cure familial hypercholesterolemia (fh) in patients either have defective ldlr or have defective immune systems attack protein. since vldlr non-immunogenic not initiate immune response, able function under defective immune systems. in addition, being apoe, major ligand of vldlr, leading genetic risk factor alzheimer’s disease, vldlr may play role in modulating risk of disorder. vldlr has been shown reduce chances of premature heart disease , stroke because vldlr clears out lipoprotein (lp(a)), major inherited risk factor these diseases.

type 1 lissencephaly

type lissencephaly, or agyria-pachygyria, rare developmental disorder characterized absence of gyri , sulci in brain. these severe malformations result of aberrant neuronal migration. in classical type lissencephaly, neuronal migration begins unable continue completion. process disrupted alterations several genes, including vldlr, dcx, arx, tuba1a, reln , lis1. severity of type lissencephaly therefore varies mutation type. homozygous deletion affecting vldlr gene results in low degree of cortical thickening , absence of cell-sparse zone. cell-sparse zone describes region between outer , inner cortical layers of arrested neurons. in addition, type 1 lissencephaly closely associated cerebellar hypoplasia.

vldlr-associated cerebellar hypoplasia

disequilibrium syndrome (des) first described in 1970s non-progressive, neurological disorder. in 2005 study, des renamed vldlr-associated cerebellar hypoplasia (vldlrch) after cause linked disruption in vldlr gene. @ least 6 mutations affecting homozygous recessive allele of vldlr gene have been identified , found cause vldlrch. several of these mutations have been localized specific exons encoding gene. 1 such mutation cytosine thymine transition @ base pair 1342 in exon 10 causes substitution @ arg448 termination signal. likewise, there evidence of cytosine thymine transition @ base pair number 769 in exon 5 causes substitution @ arg257 termination signal. third known mutation caused homozygous 1-base pair deletion in exon 17 causes frameshift , premature termination in o-linked sugar domain. such alterations vldlr gene prevent production of vldlr , therefore termed loss-of-function mutations. recognized symptoms of vldlrch moderate-to-severe intellectual disability, seizures, dysarthria, strabismus , delayed locomotion. in cases, children vldlrch learn walk late in development after age of 6 years, or never learn walk independently. frequency of disorder unknown because diagnosis of vldlrch difficult using imaging techniques. associated parental consanguinity , found in secluded communities such hutterites , inbred families iran , turkey.

atherosclerosis

atherosclerosis marked excessive accumulation of cholesterol macrophages, leading transformation foam cells. accumulation of cholesterol caused dysregulation of cholesterol influx , efflux. since macrophages not have ability limit influx of cholesterol, balance dependent on efflux pathways. vldlr expressed macrophages, , functions in uptake of native lipoproteins. uniquely, vldlr not respond cholesterol loading, due lack of feedback mechanisms. inability control uptake of native lipoproteins makes vldlr pro-atherogenic factor. characteristic supported results 2005 study, in reintroduction of vldlr vldlr knockout mice led increased atherosclerotic lesion development.