The human peripheral benzodiazepine receptor gene: Cloning and characterization of alternative splicing in normal tissues and in a patient with congenital lipoid adrenal hyperplasia
- Univ. of California, San Francisco, CA (United States)
- Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)
The mitochondrial benzodiazepine receptor (mBzR) appears to be a key factor in the flow of cholesterol into mitochondia to permit the initiation of steroid hormone synthesis. The mBzR consists of three components; the 18-kDa component on the outer mitochondrial membrane appears to contain the benzodiazepine binding site, and is hence often termed the peripheral benzodiazepine receptor (PBR). Using a cloned human PBR cDNA as probe, the authors have cloned the human PBR gene. The 13-kb gene is divided into four exons, with exon 1 encoding only a short 5[prime] untranslated segment. The 5[prime] flanking DNA lacks TATA and CAAT boxes but contains a cluster of SP-1 binding sites, typical of [open quotes]housekeeping[close quotes] genes. The encoded PBR mRNA is alternately spliced into two forms: [open quotes]authentic[close quotes] PBR mRNA retains all four exons, while a short form termed PBR-S lacks exon 2. While PBR-S contains a 102-codon open reading frame with a typical initiator sequence, the reading frame differs from that of PBR, so that the encoded protein is unrelated to PBR. RT-PCR and RNase protection experiments confirm that both PBR and PBR-S are expressed in all tissues examined and that expression of PBR-S is about 10 times the level of PBR. Expression of PBR cDNA in pCMV5 vectors transfected into COS-1 cells resulted in increased binding of [[sup 3]H]PK11195, but expression of PBR-S did not. It has been speculated that patients with congenital lipoid adrenal hyperplasia, who cannot make any steroids, might have a genetic lesion in mBzR. RT-PCR analysis of testicular RNA from such a patient, sequencing of the cDNA, and blotting analysis of genomic DNA all indicate that the gene and mRNA for the PBR component of mBzR are normal in this disease. 36 refs., 6 figs.
- OSTI ID:
- 6975691
- Journal Information:
- Genomics; (United States), Vol. 18:3; ISSN 0888-7543
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ADRENAL GLANDS
METABOLIC DISEASES
GENES
DNA SEQUENCING
DNA-CLONING
MITOCHONDRIA
BIOLOGICAL PATHWAYS
RECEPTORS
STEROIDS
BIOSYNTHESIS
BODY
CELL CONSTITUENTS
CLONING
DISEASES
DNA HYBRIDIZATION
ENDOCRINE GLANDS
GLANDS
HYBRIDIZATION
MEMBRANE PROTEINS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
STRUCTURAL CHEMICAL ANALYSIS
SYNTHESIS
550400* - Genetics