Combined effect of mutations of the GH1 gene and its proximal promoter region in a child with growth hormone neurosecretory dysfunction (GHND)

摘要

Mutational analysis of the growth hormone 1 (GH1) gene and its promoter in a patient with GH neurosecretory dysfunction (GHND) revealed a heterozygous new deletion of one base 7-bp downstream from the 3′-splice site of exon 4 (IVS4’del+7) of the GH1 gene and two new heterozygous mutations at sites ?135 and ?138 of the GH1 promoter. In addition, two polymorphisms at sites ?301 and ?308 of the GH1 promoter were observed. All other family members had either the ?301/?308 polymorphisms or the IVS4’del+7 mutation, but none had both. The IVS4’del+7 mutation located close to the splice donor site possibly interferes with the success of the splicing process, or the mutant transcripts are highly unstable because of nonsense-mediated mRNA decay. The ?135/?138 mutations, albeit in close proximity to a putative Pit-1 recognition site, do not seem to affect binding of this transcription factor. The combination of the two polymorphisms, ?301/?308, results in significantly reduced DNA-binding activity as monitored by electrophoretic mobility-shift assay. Transcription factor recognition site analysis of the GH1 promoter (MatInspector) revealed that HES1, one of the effectors of the Notch signalling system, is the only transcription factor whose binding is expected to be disrupted by each haplotype or by their combination. We provide evidence that the combination of ?301/?308 polymorphisms with the IVS4’del+7 mutation in a GHND patient probably accounts for the reduced amount of growth hormone spontaneously secreted from his pituitary gland and for the severe growth delay.