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

Abstract

Context and objective Growth hormone insensitivity with immune dysfunction caused by signal transducer and activator of transcription 5B (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 laboratorial evaluations in 52 relatives of 2 previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1,104 adult control individuals from the same region in Brazil and identified 5 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 7 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 IGF-1 (p=0.028) and IGFBP-3 (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 −1.4 ± 0.8 when compared with population-matched controls (p < 0.001). Conclusions STAT5B mutations in heterozygous state have a significant negative impact on height (approximately 3.9 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.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…Most have an additional immunodeficiency and pulmonary fibrosis (56). Heterozygosity for a STAT5B mutation leads to a slightly lower height (57).…”

A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency

“…These observations suggest that haploinsufficiency of IGF1 may be one of the genetic causes of children presenting with moderate short stature who may be initially registered as idiopathic short stature (ISS) or as small for gestational age (SGA) with failure to catch-up growth. Such gene-dose effect has also been documented for IGFALS and STAT5B mutations (17, 18).…”

Genetic causes of isolated short stature

“…Homozygous inactivating STAT5B mutations cause the classical phenotype of GH insensitivity associated with immunodeficiency (mainly eczema and chronic pulmonary disease). Relatives of autosomal recessive STAT5B deficient patients who carry STAT5B mutations usually have heights within the low normal range (41).…”