Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation

Chatterjee, Sumana; Shapiro, Lucy; Rose, Stephen; Mushtaq, Talat; Clayton, Peter E.; Ten, Svetlana; Bhangoo, Amrit; Kumbattae, Uma; Dias, Renuka; Savage, Martin O.; Metherell, Louise A.; Storr, Helen L

doi:10.1530/eje-18-0042

Cited by 15 publications

(19 citation statements)

References 35 publications

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“…The height SDS of 20 GHR 6Ψ patients previously described (21) varied between −1.7 and −5.9 with IGF1 SDS between −1.0 and −6.8. Additionally, 50% patients had 'classical' GHI facial features and the remainder had completely normal facial appearance (21).…”

Section: Introductionmentioning

confidence: 83%

“…Milder or 'non-classical' GHI cases are being increasingly recognised owing to advent of next generation sequencing techniques and an increased awareness of this group of disorders. Other molecular defects of the GH-IGF1 axis that cause 'non-classical' or milder GHI phenotypes include dominant negative GHR (38,39,40,41) and STAT5B (42) gene mutations, heterozygous IGF1 (43,44,45), IGF2 (46,47) and IGFALS (48,49) mutations, homozygous PAPPA2 (6) mutations and the GHR pseudoexon (6Ψ) mutation (18,19,20,21). Non-classical GHI is an important clinical entity and the prevalence may be higher than classical GHI (2).…”

Section: Discussionmentioning

confidence: 99%

“…In 2013, Walenkamp et al described two further 6Ψ patients with growth failure followed by partial catch-up growth without treatment (20). We recently reported the spectrum of clinical and biochemical features in 20 6Ψ subjects, which included eleven previously reported individuals and nine additional patients (21).…”

Section: Introductionmentioning

confidence: 92%

“…GHR 6Ψ mutation patients exhibit a wide spectrum of clinical and biochemical variability, even between individuals within the same kindred (21). The height SDS of 20 GHR 6Ψ patients previously described (21) varied between −1.7 and −5.9 with IGF1 SDS between −1.0 and −6.8. Additionally, 50% patients had 'classical' GHI facial features and the remainder had completely normal facial appearance (21).…”

Section: Introductionmentioning

confidence: 95%

“…The subjects were diagnosed with homozygous intronic GHR 6Ψ mutations at our centre between 2001 and 2014 (18,19,21). The referring physicians completed a proforma detailing the clinical and biochemical details at the time of DNA sampling for genetic analysis (21) and was prior to starting any growth promoting therapy. Height measurements were obtained using a wall-mounted stadiometer.…”

Section: Subjectsmentioning

confidence: 99%

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GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Chatterjee

Cottrell

Rose

et al. 2020

Endocrine Connections

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Objectives The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this. Methods 6Ψ-GHR and WT-GHR mRNA transcripts of four 6Ψ patients (height SDS −4.2 to −3.1) and one control fibroblast 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 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing. Results RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not in the control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ: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 six genes were detected, but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients. Conclusion Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ: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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Section: Introductionmentioning

confidence: 83%