Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation

Jürgen Klammt, David Neumann, Evelien F. Gevers, Shayne F. Andrew, I. David Schwartz, Denise Rockstroh, Roberto Colombo, Marco Sanchez, Doris Vokurkova, Julia Kowalczyk, Louise A. Metherell, Ronald (Ron) Rosenfeld, Roland Pfäffle, Mehul T. Dattani, Andrew Dauber, Vivian Hwa

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article number8329
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Laron Syndrome
pituitary hormones
mutations
Transducers
Growth Hormone
Lung
Mutation
Germ-Line Mutation
causes
Immune system
sensitivity
Eczema
transducers
Response Elements
Somatomedins
Transcription
Growth
Immunoglobulin E
Tyrosine
immune systems

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Klammt, J., Neumann, D., Gevers, E. F., Andrew, S. F., Schwartz, I. D., Rockstroh, D., ... Hwa, V. (2018). Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nature Communications, 9(1), [8329]. https://doi.org/10.1038/s41467-018-04521-0

Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. / Klammt, Jürgen; Neumann, David; Gevers, Evelien F.; Andrew, Shayne F.; Schwartz, I. David; Rockstroh, Denise; Colombo, Roberto; Sanchez, Marco; Vokurkova, Doris; Kowalczyk, Julia; Metherell, Louise A.; Rosenfeld, Ronald (Ron); Pfäffle, Roland; Dattani, Mehul T.; Dauber, Andrew; Hwa, Vivian.

In: Nature Communications, Vol. 9, No. 1, 8329, 01.12.2018.

Research output: Contribution to journalArticle

Klammt, J, Neumann, D, Gevers, EF, Andrew, SF, Schwartz, ID, Rockstroh, D, Colombo, R, Sanchez, M, Vokurkova, D, Kowalczyk, J, Metherell, LA, Rosenfeld, RR, Pfäffle, R, Dattani, MT, Dauber, A & Hwa, V 2018, 'Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation', Nature Communications, vol. 9, no. 1, 8329. https://doi.org/10.1038/s41467-018-04521-0
Klammt, Jürgen ; Neumann, David ; Gevers, Evelien F. ; Andrew, Shayne F. ; Schwartz, I. David ; Rockstroh, Denise ; Colombo, Roberto ; Sanchez, Marco ; Vokurkova, Doris ; Kowalczyk, Julia ; Metherell, Louise A. ; Rosenfeld, Ronald (Ron) ; Pfäffle, Roland ; Dattani, Mehul T. ; Dauber, Andrew ; Hwa, Vivian. / Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. In: Nature Communications. 2018 ; Vol. 9, No. 1.
@article{ca478bc16b6e4118bd6df7e1a8ba79e4,
title = "Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation",
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.",
author = "J{\"u}rgen Klammt and David Neumann and Gevers, {Evelien F.} and Andrew, {Shayne F.} and Schwartz, {I. David} and Denise Rockstroh and Roberto Colombo and Marco Sanchez and Doris Vokurkova and Julia Kowalczyk and Metherell, {Louise A.} and Rosenfeld, {Ronald (Ron)} and Roland Pf{\"a}ffle and Dattani, {Mehul T.} and Andrew Dauber and Vivian Hwa",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-04521-0",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation

AU - Klammt, Jürgen

AU - Neumann, David

AU - Gevers, Evelien F.

AU - Andrew, Shayne F.

AU - Schwartz, I. David

AU - Rockstroh, Denise

AU - Colombo, Roberto

AU - Sanchez, Marco

AU - Vokurkova, Doris

AU - Kowalczyk, Julia

AU - Metherell, Louise A.

AU - Rosenfeld, Ronald (Ron)

AU - Pfäffle, Roland

AU - Dattani, Mehul T.

AU - Dauber, Andrew

AU - Hwa, Vivian

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85047851039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047851039&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-04521-0

DO - 10.1038/s41467-018-04521-0

M3 - Article

C2 - 29844444

AN - SCOPUS:85047851039

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 8329

ER -