TY - JOUR
T1 - A novel missense mutation in the SH2 domain of the STAT5b gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease
AU - Scaglia, Paula A.
AU - Martínez, Alicia S.
AU - Feigerlová, Eva
AU - Bezrodnik, Liliana
AU - Gaillard, María Isabel
AU - Di Giovanni, Daniela
AU - Ballerini, María Gabriela
AU - Jasper, Héctor G.
AU - Heinrich, Juan J.
AU - Fang, Peng
AU - Domené, Horacio M.
AU - Rosenfeld, Ron G.
AU - Hwa, Vivian
PY - 2012/5
Y1 - 2012/5
N2 - Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Promissense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. Patient: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 sd score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD. Results: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the βD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-7. The phosphorylated p.Phe646Ser, however, could not drive transcription. Conclusion: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 βD' strand for full STAT5b transcriptional activities. Whetherthe phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.
AB - Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Promissense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. Patient: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 sd score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD. Results: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the βD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-7. The phosphorylated p.Phe646Ser, however, could not drive transcription. Conclusion: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 βD' strand for full STAT5b transcriptional activities. Whetherthe phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.
UR - http://www.scopus.com/inward/record.url?scp=84860716887&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860716887&partnerID=8YFLogxK
U2 - 10.1210/jc.2011-2554
DO - 10.1210/jc.2011-2554
M3 - Article
C2 - 22419735
AN - SCOPUS:84860716887
SN - 0021-972X
VL - 97
SP - E830-E839
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -