Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 107, Issue 1, Pages E401-E416Publisher
ENDOCRINE SOC
DOI: 10.1210/clinem/dgab550
Keywords
short stature; growth hormone insensitivity; GHR 6 Omega pseudoexon; severe primary IGF-1 deficiency
Categories
Funding
- Barts Charity Large Project Grant [MRC0161]
- 2018 European Society for Paediatric Endocrinology Research Fellowship
- Sandoz Limited UK research grant [1010180]
- National Institute for Health Research [NIHR300098]
- National Institutes of Health Research (NIHR) [NIHR300098] Funding Source: National Institutes of Health Research (NIHR)
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This study identified a novel GHR 6 Omega pseudoexon variant that causes severe growth failure in individuals with growth hormone insensitivity. This represents a new mechanism of Laron syndrome and the first deep intronic variant identified to cause severe postnatal growth failure.
Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies. Objective: This work aims to identify the genetic cause of growth failure in 3 classical GHI individuals. Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6 Omega pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. Results: We identified a novel homozygous intronic GHR variant (g.5:42700940 T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6 Psi GHR pseudoexon mutation in the index patient.Two siblings also harbored the novel intronic 6 Omega pseudoexon GHR variant in compound heterozygosity with the known GHRc.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6 Omega pseudoexon not identified in wild-type constructs. Inclusion of the 6 Omega pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains.The truncated 6 Omega pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. Conclusion: Novel GHR 6 Omega pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure.The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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