The growth hormone receptor gene mutation of a japanese patient with laron syndrome

Abstract

SummaryDeletions and point mutations of the growth hormone (GH) receptor gene (GHR) have been identified in patients with Laron syndrome. We report the first detection of the GHR mutation among Japanese patients with Laron syndrome. Using the Japanese female patient's genomic DNA as a template, all exons and flanking portions of introns of GHR were amplified by polymerase chain reaction (PCR). Sequencing of the PCR products showed that the patient was homozygous for a G to A substitution at the first position of intron 4. This substitution was same as that detected in a Spanish patient and a north European patient. The base change occurred at the 5' splice consensus sequence of intron 4, resulting in the abolition of a BanI restriction site. Since this substitution was not detected by a BanI restriction analysis in 85 control individuals, it is more likely a disease-related splice mutation than a polymorphism. The mutation in our patient was predicted to destroy the original 5" splice site of intron 4 of GHR and to produce a new cryptic splice site, leading to abnormal mRNA processing and a lack of GH binding activity of GH-binding protein (GHBP).

A Novel <b><i>GHR</i></b> Intronic Variant, <b><i>c.266+83G>T</i></b>, Activates a Cryptic 5′ Splice Site Causing Severe GHR Deficiency and Classical GH Insensitivity Syndrome

“…To date, the majority of reported GHR splice site mutations (12 out of 15) disrupt the native 5′ or 3′ splice sites [1,22], inevitably resulting in exon skipping. Indeed, this was the case for the previously described intron 4 c.266+1G>A mutation which destroyed the normal invariant dinucleotide at the 5′ donor splice site [23,24]. Only 3 splicing mutations that activate cryptic splice sites have been previously described, all involving cryptic 5′ splice sites encoding for the GHR extracellular domain (fig.…”