Abstract
Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.
Highlights
Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, postnatal growth impaired
For the p.Gln474Arg and p.Ala478Val variants, located within the DNA-binding domain (DBD) module, we evaluated whether DNA binding might be impaired, employing standard gel-shift electrophoretic mobility shift assay (EMSA) analysis
We report the identification of three novel germline STAT5B missense variants, with demonstrable dominant-negative effects, associated with short stature and mild growth hormone insensitivity syndrome (GHIS) in three unrelated families
Summary
Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, postnatal growth impaired. We report dominantnegative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. We demonstrate that specific heterozygous STAT5B germline mutations exert dominant-negative effects resulting in STAT5B deficiency clinically characterized by significant postnatal growth impairment, mild GH insensitivity, eczema, and elevated IgE
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