Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene
Screening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase...
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| Format: | Article |
| Language: | English |
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Elsevier
1999-02-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520333599 |
| _version_ | 1818669395233210368 |
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| author | Olaug K. Rødningen Serena Tonstad Jheem D. Medh David A. Chappell Leiv Ose Trond P. Leren |
| author_facet | Olaug K. Rødningen Serena Tonstad Jheem D. Medh David A. Chappell Leiv Ose Trond P. Leren |
| author_sort | Olaug K. Rødningen |
| collection | DOAJ |
| description | Screening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase chain reaction and cDNA sequencing. These analyses identified a 4.8 kb in-frame deletion of exons 2 and 3, where exon 1 was spliced to exon 4. This deletion is expected to produce a receptor that has lost the two first cysteine-rich repeats of the ligand-binding domain. Previously published data of in vitro site-directed mutagenesis has shown that binding of LDL to such a receptor is reduced to 70% of normal. A mild phenotype in our FH homozygote is consistent with that observation. In contrast, heterozygotes carrying this deletion have a relatively more severe phenotype that is comparable to that of heterozygotes carrying a null-allele. A severe phenotype was also found in a compound heterozygote carrying this deletion. Possible mechanisms for this phenotypic variability are discussed.—Rødningen, O. K., S. Tonstad, J. D. Medh, D. A. Chappell, L. Ose, and T. P. Leren. Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene. J. Lipid Res. 1999. 40: 213–220. |
| first_indexed | 2024-12-17T06:51:32Z |
| format | Article |
| id | doaj.art-5f286caf9e3243638a3beafa53264f88 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T06:51:32Z |
| publishDate | 1999-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-5f286caf9e3243638a3beafa53264f882022-12-21T21:59:34ZengElsevierJournal of Lipid Research0022-22751999-02-01402213220Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor geneOlaug K. Rødningen0Serena Tonstad1Jheem D. Medh2David A. Chappell3Leiv Ose4Trond P. Leren5To whom correspondence should be addressed.; Department of Medical Genetics, Ullevål University Hospital, N-0407 Oslo, Norway; Medinnova/MSD Cardiovascular Research Centre, Rikshospitalet, N-0027 Oslo, NorwayDepartment of Preventive Cardiology, Ullevål University Hospital, N-0407 Oslo, NorwayUniversity of Iowa College of Medicine, Iowa City, IA 52242, USAUniversity of Iowa College of Medicine, Iowa City, IA 52242, USALipid Clinic, Rikshospitalet, N-0027 Oslo, NorwayMedinnova/MSD Cardiovascular Research Centre, Rikshospitalet, N-0027 Oslo, Norway; Medinnova/MSD Cardiovascular Research Centre, Rikshospitalet, N-0027 Oslo, NorwayScreening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase chain reaction and cDNA sequencing. These analyses identified a 4.8 kb in-frame deletion of exons 2 and 3, where exon 1 was spliced to exon 4. This deletion is expected to produce a receptor that has lost the two first cysteine-rich repeats of the ligand-binding domain. Previously published data of in vitro site-directed mutagenesis has shown that binding of LDL to such a receptor is reduced to 70% of normal. A mild phenotype in our FH homozygote is consistent with that observation. In contrast, heterozygotes carrying this deletion have a relatively more severe phenotype that is comparable to that of heterozygotes carrying a null-allele. A severe phenotype was also found in a compound heterozygote carrying this deletion. Possible mechanisms for this phenotypic variability are discussed.—Rødningen, O. K., S. Tonstad, J. D. Medh, D. A. Chappell, L. Ose, and T. P. Leren. Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene. J. Lipid Res. 1999. 40: 213–220.http://www.sciencedirect.com/science/article/pii/S0022227520333599deletionfamilial hypercholesterolemiahomozygous FHlow density lipoprotein receptor |
| spellingShingle | Olaug K. Rødningen Serena Tonstad Jheem D. Medh David A. Chappell Leiv Ose Trond P. Leren Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene Journal of Lipid Research deletion familial hypercholesterolemia homozygous FH low density lipoprotein receptor |
| title | Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene |
| title_full | Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene |
| title_fullStr | Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene |
| title_full_unstemmed | Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene |
| title_short | Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene |
| title_sort | phenotypic consequences of a deletion of exons 2 and 3 of the ldl receptor gene |
| topic | deletion familial hypercholesterolemia homozygous FH low density lipoprotein receptor |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520333599 |
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