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

PAULA A. SCAGLIA; ALICIA S. MARTÍNEZ; EVA FEIGERLOVÁ; LILIANA BEZRODNIK; MARÍA ISABEL GAILLARD; DANIELA DI GIOVANNI; MARÍA GABRIELA BALLERINI; HÉCTOR G. JASPER; JUAN J. HEINRICH; PENG FANG; HORACIO M. DOMENÉ; RON G. ROSENFELD; VIVIAN HWA

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2012 vol. 97 p. 830 - 839

0021-972X

Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported ina patientwhocarried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, resultsin a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immunedysregulation manifesting as progressive worsening of pulmonary function.Patient: The new patient presented with severe cutaneous eczema, episodic infections in the firstyears of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, butsevere pulmonary symptoms were notably absent. She concomitantly exhibited pronouncedgrowth failure, reaching an adult height of 124.7 cm [
5.90 SD score (SDS)]. Endocrine evaluations(normal provocativeGHtests; low serum IGF-I,
3.7 SDS, and IGF-binding protein-3,
4.5 SDS) wereconsistent with GHI and IGFD.Results: Analysis of the STAT5B gene revealed a novel homozygous missense mutation,p.Phe646Ser, located within the
D strand of the SH2 domain. Reconstitution studies demonstratedexpression of the p.Phe646Ser variant was less robust than wild type but, in contrast to thepreviously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response toGH and interferon-. The phosphorylated p.Phe646Ser, however, could not drive transcription.Conclusion: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristicsof STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack oftranscriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b forregulating the expression of IGF1 and provides insights into the importance of the SH2
D strand forfull STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functionsthat prevented pulmonary distress remains unresolved.