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

Authors
Scalco, Renata C.; Hwa, Vivian; Domene, Horacio Mario; Jasper, Hector Guillermo; Belgorosky, Alicia; Marino, Roxana; Pereira, Alberto M.; Tonelli, Carlos A.; Wit, Jan M.; Rosenfeld, Ron G.; Jorge, Alexander A. L.
Publication Year
2015
Language
English
Format
article
Status
Published version
Description
Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessivecondition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mildheight 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 describedBrazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained heightdata and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional familiesharboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data fromfirst-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data fromheterozygous individuals and non-carriers were compared.Results: Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrierrelatives (PZ0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (PZ0.028) andIGFBP3 (PZ0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygousSTAT5B mutations had an average height SDS of K1.4G0.8 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 effectis milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support thehypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.
Fil: Scalco, Renata C.. Universidade de Sao Paulo; Brasil
Fil: Hwa, Vivian. Cincinnati Center for Growth Disorders; Estados Unidos
Fil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Marino, Roxana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Pereira, Alberto M.. Leiden University Medical Center; Países Bajos
Fil: Tonelli, Carlos A.. Universidade do Extremo Sul Catarinense; Brasil
Fil: Wit, Jan M.. Leiden University Medical Center; Países Bajos
Fil: Rosenfeld, Ron G.. Oregon Health and Science University; Estados Unidos
Fil: Jorge, Alexander A. L. . Universidade de Sao Paulo; Brasil
Subject
STAT5B
heterozygous
mutations
Endocrinología y Metabolismo
Medicina Clínica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Open access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/8275