TY - JOUR
T1 - The LDL receptor locus in familial hypercholesterolemia
T2 - Multiple mutations disrupt transport and processing of a membrane receptor
AU - Tolleshaug, Helge
AU - Hobgood, Kim K.
AU - Brown, Michael S.
AU - Goldstein, Joseph L.
N1 - Funding Information:
Claudia Stewart and Martin Smith provided excellent technical assistance. We thank Edith Womack and Deborah Thompson for their able assistance in growing fibroblasts. We are especially grateful to Drs. Francois Dairou and Professor J. L. de Gennes for their help in obtaining skin biopsies on the family members of several of the FH homozygotes reported in this study. This research was support by a research grant from the National Institutes of Health. H. T. is the recipient of a fellowship from the Fogarty International Center of the National Institutes of Health.
PY - 1983/3
Y1 - 1983/3
N2 - The receptor for low-density lipoprotein (LDL) is synthesized as a 120 kd precursor that undergoes a 40 kd posttranslational increase in apparent molecular weight en route to the cell surface. We describe seven mutations that disrupt synthesis, processing and transport of the receptor in fibroblasts from 77 subjects with the clinical diagnosis of homozygous familial hypercholesterolemia. One mutation obliterates synthesis of immunoprecipitable precursor. Three mutations specify precursors (100, 120 and 135 kd) that fail to undergo normal processing and fail to reach the cell surface. The other three mutations specify precursors (100, 120, and 170 kd) that undergo a normal 40 kd increase in molecular weight and reach the surface, but do not bind LDL normally. Pedigree studies show that each mutation segregates as an allele at the LDL receptor locus. These data imply that signals for transport of receptors from endoplasmic reticulum to the cell surface are contained within the amino acid sequences of the receptors, and that mutations affecting these sequences can disrupt receptor transport.
AB - The receptor for low-density lipoprotein (LDL) is synthesized as a 120 kd precursor that undergoes a 40 kd posttranslational increase in apparent molecular weight en route to the cell surface. We describe seven mutations that disrupt synthesis, processing and transport of the receptor in fibroblasts from 77 subjects with the clinical diagnosis of homozygous familial hypercholesterolemia. One mutation obliterates synthesis of immunoprecipitable precursor. Three mutations specify precursors (100, 120 and 135 kd) that fail to undergo normal processing and fail to reach the cell surface. The other three mutations specify precursors (100, 120, and 170 kd) that undergo a normal 40 kd increase in molecular weight and reach the surface, but do not bind LDL normally. Pedigree studies show that each mutation segregates as an allele at the LDL receptor locus. These data imply that signals for transport of receptors from endoplasmic reticulum to the cell surface are contained within the amino acid sequences of the receptors, and that mutations affecting these sequences can disrupt receptor transport.
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U2 - 10.1016/0092-8674(83)90079-X
DO - 10.1016/0092-8674(83)90079-X
M3 - Article
C2 - 6299582
AN - SCOPUS:0020522133
SN - 0092-8674
VL - 32
SP - 941
EP - 951
JO - Cell
JF - Cell
IS - 3
ER -