STAT5B mutations in heterozygous state have negative impact on height: Another clue in human stature heritability

Renata C. Scalco, Vivian Hwa, Horacio M. Domené, Héctor G. Jasper, Alicia Belgorosky, Roxana Marino, Alberto M. Pereira, Carlos A. Tonelli, Jan M. Wit, Ronald (Ron) Rosenfeld, Alexander A L Jorge

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424-427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424-427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of K1.4±0.8 when compared with population-matched controls (P<0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.

Original languageEnglish (US)
Pages (from-to)291-296
Number of pages6
JournalEuropean Journal of Endocrinology
Volume173
Issue number3
DOIs
StatePublished - Sep 1 2015

Fingerprint

Mutation
Population Control
Brazil
Siblings
Reference Values
Genotype
Phenotype
Growth
Serum
Genes

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Scalco, R. C., Hwa, V., Domené, H. M., Jasper, H. G., Belgorosky, A., Marino, R., ... Jorge, A. A. L. (2015). STAT5B mutations in heterozygous state have negative impact on height: Another clue in human stature heritability. European Journal of Endocrinology, 173(3), 291-296. https://doi.org/10.1530/EJE-15-0398

STAT5B mutations in heterozygous state have negative impact on height : Another clue in human stature heritability. / Scalco, Renata C.; Hwa, Vivian; Domené, Horacio M.; Jasper, Héctor G.; Belgorosky, Alicia; Marino, Roxana; Pereira, Alberto M.; Tonelli, Carlos A.; Wit, Jan M.; Rosenfeld, Ronald (Ron); Jorge, Alexander A L.

In: European Journal of Endocrinology, Vol. 173, No. 3, 01.09.2015, p. 291-296.

Research output: Contribution to journalArticle

Scalco, RC, Hwa, V, Domené, HM, Jasper, HG, Belgorosky, A, Marino, R, Pereira, AM, Tonelli, CA, Wit, JM, Rosenfeld, RR & Jorge, AAL 2015, 'STAT5B mutations in heterozygous state have negative impact on height: Another clue in human stature heritability', European Journal of Endocrinology, vol. 173, no. 3, pp. 291-296. https://doi.org/10.1530/EJE-15-0398
Scalco, Renata C. ; Hwa, Vivian ; Domené, Horacio M. ; Jasper, Héctor G. ; Belgorosky, Alicia ; Marino, Roxana ; Pereira, Alberto M. ; Tonelli, Carlos A. ; Wit, Jan M. ; Rosenfeld, Ronald (Ron) ; Jorge, Alexander A L. / STAT5B mutations in heterozygous state have negative impact on height : Another clue in human stature heritability. In: European Journal of Endocrinology. 2015 ; Vol. 173, No. 3. pp. 291-296.
@article{af728bc94c574c0e862f6f7fa81bb378,
title = "STAT5B mutations in heterozygous state have negative impact on height: Another clue in human stature heritability",
abstract = "Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424-427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424-427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of K1.4±0.8 when compared with population-matched controls (P<0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.",
author = "Scalco, {Renata C.} and Vivian Hwa and Domen{\'e}, {Horacio M.} and Jasper, {H{\'e}ctor G.} and Alicia Belgorosky and Roxana Marino and Pereira, {Alberto M.} and Tonelli, {Carlos A.} and Wit, {Jan M.} and Rosenfeld, {Ronald (Ron)} and Jorge, {Alexander A L}",
year = "2015",
month = "9",
day = "1",
doi = "10.1530/EJE-15-0398",
language = "English (US)",
volume = "173",
pages = "291--296",
journal = "European Journal of Endocrinology",
issn = "0804-4643",
publisher = "BioScientifica Ltd.",
number = "3",

}

TY - JOUR

T1 - STAT5B mutations in heterozygous state have negative impact on height

T2 - Another clue in human stature heritability

AU - Scalco, Renata C.

AU - Hwa, Vivian

AU - Domené, Horacio M.

AU - Jasper, Héctor G.

AU - Belgorosky, Alicia

AU - Marino, Roxana

AU - Pereira, Alberto M.

AU - Tonelli, Carlos A.

AU - Wit, Jan M.

AU - Rosenfeld, Ronald (Ron)

AU - Jorge, Alexander A L

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424-427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424-427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of K1.4±0.8 when compared with population-matched controls (P<0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.

AB - Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424-427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424-427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of K1.4±0.8 when compared with population-matched controls (P<0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.

UR - http://www.scopus.com/inward/record.url?scp=84940662190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940662190&partnerID=8YFLogxK

U2 - 10.1530/EJE-15-0398

DO - 10.1530/EJE-15-0398

M3 - Article

C2 - 26034074

AN - SCOPUS:84940662190

VL - 173

SP - 291

EP - 296

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

SN - 0804-4643

IS - 3

ER -