UT Southwestern Researchers Find Gene for Inherited Form of High Cholesterol

Apr 26, 2001, 01:00 ET from UT Southwestern Medical Center at Dallas

    DALLAS, April 26 /PRNewswire/ -- Researchers at UT Southwestern Medical
 Center at Dallas have located the gene that, when mutated, is responsible for
 autosomal recessive hypercholesterolemia (ARH), an inherited form of high
 cholesterol characterized by low-density lipoprotein levels of 350 to
 600 milligrams per deciliter.
     This disorder, which results in the development of premature coronary
 artery disease and accumulation of cholesterol in skin and tendons, is rare,
 but understanding its genesis may lead to the development of new treatments
 for high blood levels of cholesterol.
     Scientists at UT Southwestern located the ARH gene on chromosome 1p35 and
 found six mutations in the gene.  The gene encodes a new adaptor protein,
 which the scientists named ARH.  The results of the study are published in the
 May issue of Science.
     "This gene is a new key player in the clearance mechanism of LDL from the
 body.  We know it's important because when it is mutated, people have very
 high plasma cholesterol levels," said Dr. Helen Hobbs, chief of clinical
 genetics, director of the Eugene McDermott Center for Human Growth and
 Development, and senior investigator of the study.
     Under normal conditions, low-density lipoprotein receptors (LDLR), which
 are found in the liver, remove LDL cholesterol from the blood.  More than
 70 percent of LDL cholesterol is removed from the blood by these receptors.
 Mutations in the LDLR gene cause the autosomal dominant disorder familial
 hypercholesterolemia, a discovery made by UT Southwestern Nobel laureates Drs.
 Michael Brown and Joseph Goldstein.
     Researchers have known that ARH was not caused by mutations in the LDLR,
 but until now had not identified the defective gene that is responsible for
 the disorder.  Hobbs and her colleagues found that defects in ARH impair the
 function of the LDLR and arrest the body's normal ability to clear LDL
 cholesterol.
     The researchers analyzed the DNA samples of four families with ARH.  Two
 of the families were from Sardinia, where the disease is prevalent, and two
 families were from Lebanon.  The study participants had extremely high LDL-
 cholesterol levels, ranging from 350 to 600 mg/dL.  Optimal LDL-cholesterol
 levels range between 60 and 130 mg/dL.
     After mapping the gene in these families, the researchers identified the
 defective gene.  The researchers found different mutations in each of the four
 original families.  They then examined additional study participants with the
 same disorder and found that they also had mutations in the same gene.
     Two mutations in the gene account for the high frequency of the disease in
 Sardinia.  Mutations were also found in an Iranian, American and two Lebanese
 study participants.
     "We're confident that this is the gene responsible for ARH," said Hobbs.
     Dr. Jonathan Cohen, associate professor of internal medicine, co-author of
 the study and a nutrition scholar in the Center for Human Nutrition, said,
 "These findings give us insight about how cells move cholesterol around and
 how the body gets rid of it.  Once it's understood, we can manipulate the
 system more efficiently."
     Hobbs and her collaborators recently identified the defective genes
 responsible for the rare genetic disorder, sitosterolemia, an important
 finding that may lead to the development of new drugs to treat high
 cholesterol.  Hobbs was also part of the research team that, for the first
 time, identified a receptor for high-density lipoprotein (HDL) called SR-B1.
 It is the mechanism by which HDL, the "good cholesterol," is delivered to some
 cells.
     UT Southwestern researchers have discovered the defective genes in all
 four major inherited forms of hypercholesterolemia.  Brown and Goldstein,
 director of the Erik Jonsson Center for Research in Molecular Genetics and
 Human Disease and chairman of molecular genetics, respectively, discovered the
 defective gene in familial hypercholesterolemia (FH).  Dr. Scott Grundy,
 director of the Center for Human Nutrition, discovered that some patients who
 appeared to have FH actually had a mutation in a protein found on the LDL
 called apolipoprotein B.
     Other researchers involved in the most recent Science study include Dr.
 Christine Kim Garcia, an internal medicine resident and former M.D./Ph.D.
 student in molecular genetics; Dr. Nick Grishin, assistant professor in
 biochemistry and assistant investigator in the Howard Hughes Medical
 Institute; Dr. Kenneth Wilund, research fellow in internal medicine; and
 Robert Barnes, a program analyst in the Eugene McDermott Center for Human
 Growth and Development.  Other researchers, two of whom had worked previously
 with Hobbs as postdoctoral fellows, included scientists from the University of
 Rome; the University of Ferrara, Italy; the University of Sassari, Italy; the
 University of Modena and Reggioemilia, Italy; and the Bone Marrow Transplant
 Unit, Ospedale Microcitemico, Cagliari, Italy.
     The study was funded by the National Institutes of Health, the W.M. Keck
 Foundation, the Perot Foundation and the Donald W. Reynolds Foundation.
     This news release is available on our World Wide Web home page at
 http://www.utsouthwestern.edu/home_pages/news/
     To automatically receive news releases from UT Southwestern via e-mail,
 send a message to UTSWNEWS-REQUEST@listserv.swmed.edu.  Leave the subject line
 blank and in the text box, type SUB UTSWNEWS.
 
                     MAKE YOUR OPINION COUNT -  Click Here
                http://tbutton.prnewswire.com/prn/11690X80857100
 
 

SOURCE UT Southwestern Medical Center at Dallas
    DALLAS, April 26 /PRNewswire/ -- Researchers at UT Southwestern Medical
 Center at Dallas have located the gene that, when mutated, is responsible for
 autosomal recessive hypercholesterolemia (ARH), an inherited form of high
 cholesterol characterized by low-density lipoprotein levels of 350 to
 600 milligrams per deciliter.
     This disorder, which results in the development of premature coronary
 artery disease and accumulation of cholesterol in skin and tendons, is rare,
 but understanding its genesis may lead to the development of new treatments
 for high blood levels of cholesterol.
     Scientists at UT Southwestern located the ARH gene on chromosome 1p35 and
 found six mutations in the gene.  The gene encodes a new adaptor protein,
 which the scientists named ARH.  The results of the study are published in the
 May issue of Science.
     "This gene is a new key player in the clearance mechanism of LDL from the
 body.  We know it's important because when it is mutated, people have very
 high plasma cholesterol levels," said Dr. Helen Hobbs, chief of clinical
 genetics, director of the Eugene McDermott Center for Human Growth and
 Development, and senior investigator of the study.
     Under normal conditions, low-density lipoprotein receptors (LDLR), which
 are found in the liver, remove LDL cholesterol from the blood.  More than
 70 percent of LDL cholesterol is removed from the blood by these receptors.
 Mutations in the LDLR gene cause the autosomal dominant disorder familial
 hypercholesterolemia, a discovery made by UT Southwestern Nobel laureates Drs.
 Michael Brown and Joseph Goldstein.
     Researchers have known that ARH was not caused by mutations in the LDLR,
 but until now had not identified the defective gene that is responsible for
 the disorder.  Hobbs and her colleagues found that defects in ARH impair the
 function of the LDLR and arrest the body's normal ability to clear LDL
 cholesterol.
     The researchers analyzed the DNA samples of four families with ARH.  Two
 of the families were from Sardinia, where the disease is prevalent, and two
 families were from Lebanon.  The study participants had extremely high LDL-
 cholesterol levels, ranging from 350 to 600 mg/dL.  Optimal LDL-cholesterol
 levels range between 60 and 130 mg/dL.
     After mapping the gene in these families, the researchers identified the
 defective gene.  The researchers found different mutations in each of the four
 original families.  They then examined additional study participants with the
 same disorder and found that they also had mutations in the same gene.
     Two mutations in the gene account for the high frequency of the disease in
 Sardinia.  Mutations were also found in an Iranian, American and two Lebanese
 study participants.
     "We're confident that this is the gene responsible for ARH," said Hobbs.
     Dr. Jonathan Cohen, associate professor of internal medicine, co-author of
 the study and a nutrition scholar in the Center for Human Nutrition, said,
 "These findings give us insight about how cells move cholesterol around and
 how the body gets rid of it.  Once it's understood, we can manipulate the
 system more efficiently."
     Hobbs and her collaborators recently identified the defective genes
 responsible for the rare genetic disorder, sitosterolemia, an important
 finding that may lead to the development of new drugs to treat high
 cholesterol.  Hobbs was also part of the research team that, for the first
 time, identified a receptor for high-density lipoprotein (HDL) called SR-B1.
 It is the mechanism by which HDL, the "good cholesterol," is delivered to some
 cells.
     UT Southwestern researchers have discovered the defective genes in all
 four major inherited forms of hypercholesterolemia.  Brown and Goldstein,
 director of the Erik Jonsson Center for Research in Molecular Genetics and
 Human Disease and chairman of molecular genetics, respectively, discovered the
 defective gene in familial hypercholesterolemia (FH).  Dr. Scott Grundy,
 director of the Center for Human Nutrition, discovered that some patients who
 appeared to have FH actually had a mutation in a protein found on the LDL
 called apolipoprotein B.
     Other researchers involved in the most recent Science study include Dr.
 Christine Kim Garcia, an internal medicine resident and former M.D./Ph.D.
 student in molecular genetics; Dr. Nick Grishin, assistant professor in
 biochemistry and assistant investigator in the Howard Hughes Medical
 Institute; Dr. Kenneth Wilund, research fellow in internal medicine; and
 Robert Barnes, a program analyst in the Eugene McDermott Center for Human
 Growth and Development.  Other researchers, two of whom had worked previously
 with Hobbs as postdoctoral fellows, included scientists from the University of
 Rome; the University of Ferrara, Italy; the University of Sassari, Italy; the
 University of Modena and Reggioemilia, Italy; and the Bone Marrow Transplant
 Unit, Ospedale Microcitemico, Cagliari, Italy.
     The study was funded by the National Institutes of Health, the W.M. Keck
 Foundation, the Perot Foundation and the Donald W. Reynolds Foundation.
     This news release is available on our World Wide Web home page at
 http://www.utsouthwestern.edu/home_pages/news/
     To automatically receive news releases from UT Southwestern via e-mail,
 send a message to UTSWNEWS-REQUEST@listserv.swmed.edu.  Leave the subject line
 blank and in the text box, type SUB UTSWNEWS.
 
                     MAKE YOUR OPINION COUNT -  Click Here
                http://tbutton.prnewswire.com/prn/11690X80857100
 
 SOURCE  UT Southwestern Medical Center at Dallas