GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients
2020
OBJECTIVES: The homozygous GH receptor (GHR) pseudoexon (6Psi) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Psi-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this. METHODS: 6Psi-GHR and WT-GHR mRNA transcripts of 4 6Psi patient (height SDS -4.2 to -3.1) and 1 control fibroblasts were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Psi patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing. RESULTS: RT-PCR confirmed 6Psi-GHR transcript in the 6Psi patients but not control. 6Psi-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Psi:WT transcript ratios ranged from 29-71:1 for patients 1-4 and correlated negatively with height SDS (R=-0.85; p<0.001). Eight deleterious variants in 6 genes were detected but the number of gene hits did not correlate with the degree of SS in individual 6Psi patients. CONCLUSION: Variable amounts of 6Psi- and WT-GHR transcripts were identified in 6Psi patients but no 6Psi transcript was present in the control. Higher 6Psi:WT GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.
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