A novel mutation of exon 7 in growth hormone receptor mRNA in a patient with growth hormone insensitivity syndrome and neurofibromatosis type I

Abstract

Growth hormone insensitivity syndrome (GHIS), a genetic disease characterized by growth retardation combined with high serum concentration of growth hormone (GH) and low insulin-like growth factor 1 (IGF-1) levels, can be caused by mutations in the GH receptor (GHR) gene. We investigated the molecular defects in the GHR gene in a patient with neurofibromatosis type 1 (NF-1). The patient, a 2-year-old boy with NF-1, was assessed on his short stature by auxological, biochemical and molecular studies. Height of the patient and his family members were measured and compared to normal control. Serum concentrations of GH, IGF-1 and IGF-binding protein 3 (IGFBP3) in the patient were measured during a GH stimulation test. We examined the GHR gene in the patient and his parents. Genomic DNA and mRNA of the GHR gene were extracted from peripheral lymphocytes. All the exons and the flanking regions of the GHR gene were amplified by PCR, and directly sequenced. The patient's height was 75 cm (-2.89 SDS) with gradually reducing growth velocity, while the heights of the other family members were within the normal range. The GH stimulation test revealed that serum GH concentrations in the patient were much higher than those in the control group, and serum IGF-1 and IGFBP3 levels were extremely low. There was no germline mutation in the exons or the flanking regions of the patient's GHR gene. Interestingly, a deletion of 166 bases of exon 7 in the GHR mRNA was found, and it was suggested that the novel mutation resulted in premature termination (M207 fs. X8). This mutation decreases GH binding affinity to the GHR, and, thus, would be responsible for growth retardation.

A Novel mRNA Modification Mutation in a Patient With Ligneous Conjunctivitis Coexisting With Heterozygous Familial Mediterranean Fever Mutation

“…There are very few cases reported in the literature with mRNA mutations without a gene variant detected during sequence analysis of DNA. Kang et al 10 reported a case with GH insensitivity syndrome and neurofibromatosis. They did not detect any germline mutation in the exons or the flanking regions of the patient's growth hormone receptor ( GHR ) gene.…”

“…Mutations in mRNA were reported in extremely rare cases with systemic lupus erythematosus (SLE), neurofibromatosis, and growth hormone (GH) deficiency. 10–12 In nearly all cases, there were no DNA mutations in the related gene, whereas there were some variants detected in mRNA sequencing. This is the first case with LC with a normal DNA sequence, including coding and flanking regions, in which an mRNA variant was detected.…”

Reporting a novel growth hormone receptor gene variant in an Iranian consanguineous pedigree with Laron syndrome: a case report

“…3 Schematic representation of reported variants in the GHR gene and the corresponding protein structure including the signal peptide, an extracellular domain consisting of two FN3 subdomains, a transmembrane domain, and an intracellular domain. The identified variant in this study was marked in red [ 2 – 6 , 8 , 12 , 13 , 15 , 17 – 19 , 21 , 23 , 26 – 29 , 31 , 34 , 36 , 37 , 43 , 47 , 48 , 50 , 51 , 54 – 56 , 58 – 60 , 64 , 65 , 68 – 70 , 72 – 74 ] …”

Short stature related to Growth Hormone Insensitivity (GHI) in childhood

“…Finally, a deletion of 166 bases of exon 7 in the GHR mRNA was found in a patient affected by neurofibromatosis and concomitant short stature. This mutation resulted in the premature termination of the sequence and thus in a reduced GH-binding affinity to the GHR, hence determining growth failure ( 43 ).…”