摘要:

An Italian family with three children presenting with isolated growth hormone (GH) deficiency type IA is described. Restriction endonuclease analysis revealed that the cause of hGH deficiency was a 45-kb gene deletion within the hGH-chorionic somatomammotropin (CS) gene cluster, encompassing the GH-1, CS-L, CS-A, and GH-2 genes. DNA sequence analysis and polymerase chain reaction amplification between two sequences located on each side of the deletion breakpoint accurately identified the deletion breakpoints and indicated that the regulatory sequences located upstream from the TATA box of the mutant CS-B belong to the GH-2 gene. Two of the affected children developed high-titer anti-hGH antibodies after recombinant hGH treatment with secondary growth arrest, whereas the third one maintained normal growth in the presence of very low-titer antibodies. This is the first report of a large deletional mutation within the hGH-CS gene cluster accompanied by phenotypic heterogeneity in terms of growth response and antibody formation in the different patients.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We previously reported the gene deletion encoding cytochrome P-450 cholesterol side-chain cleavage enzyme (P450SCC, resulting in complete elimination of the adrenal gene expression and causing congenital adrenal hyperplasia in the rabbit. Using the rabbit congenital adrenal hyperplasia model, we investigated the wild type (wt) P-450SCCgene dose effect on gene expression in three P-450SCCgenotype animals [wt/wt, wt/mutant (mt), mt/mt] identified by Southern blot analysis. Northern blots using a rabbit P-450SCCcDNA probe revealed no detectable P-450SCCmRNA in individual adrenals of animals with congenital adrenal hyperplasia (mt/mt) and approximately half or slightly less than half the levels of the mRNA in the pooled adrenals of five heterozygous (wt/mt) newborn animals compared with the mRNA levels in the pooled adrenals of five homozygous normal (wt/wt) newborn animals. Identical P-450SCCmRNA levels were found individual adrenals of adult animals with regard to the P-450SCCgenotype, although at a higher expression level than in the newborn animals of the same genotype. Control Northern blots using human CPY21-B cDNA and cytoplasmic actin cDNA probes confirmed the accuracy and integrity of RNA. Western immunoblotting using antiovine P-450SCCantibody revealed decreased P-450SCCprotein in the adrenals of wt/mt animals at approximately half the level of the P-450SCCprotein in the adrenals of the wt/wt animals. Baseline and ACTE-stimulated serum corticosterone (B) levelsin vivowere similar between the age-matched wt/mt and wt/wt animals, whereas ACTH-stimulated B levels in adult animals were higher than those in the newborn animals irrespective of P-450SCCgenotype. These data demonstrated for the first time the presence of a wt steroidogenic enzyme gene dose effect on gene expressionin vivoat the levels of the mRNA and enzyme protein. With age, the gene dose-related gene expression was maintained, although at higher expression levels. The normal adrenal B-producing capacity in heterozygous, wt/mt animals despite the markedly decreased P-450SCCgene expression suggests the presence of either a mechanism compensating the availability of mitochondrial cholesterol substrate to overcome the decreased P-450SCCor rate-limiting effect of P-450SCCin the conversion of excess cholesterol substrate available in the adrenal mitochondria. The greater B-producing capacity under ACTH stimulation in the adult animals compared with the newborn animal irrespective of P-450SCCgenotype therefore is likely from the greater adrenal receptor capacity for ACTH rather than from the greater P-450SCCgene expression level.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID