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

Author(s):Show less -

Scalco, Renata C. ^[1] ; Hwa, Vivian ^[2] ; Domene, Horacio M. ^[3] ; Jasper, Hector G. ^[3] ; Belgorosky, Alicia ^[4] ; Marino, Roxana ^[4] ; Pereira, Alberto M. ^[5] ; Tonelli, Carlos A. ^[6] ; Wit, Jan M. ^[7] ; Rosenfeld, Ron G. ^[8] ; Jorge, Alexander A. L. ^[1]

Affiliation

^[1] Univ Sao Paulo, Lab Endocrinol Celular & Mol LIM 25, Unidade Endocrinol Genet, Disciplina Endocrinol, Fac Med, BR-01246903 Sao Paulo, SP - Brazil

^[2] Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 45229 - USA

^[3] Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol Dr Cesar Bergada CEDIE, CONICET, FEI, Div Endocrinol, Buenos Aires, DF - Argentina

^[4] Hosp Pediat Garrahan, Endocrine Serv, RA-1881 Buenos Aires Pozos - Argentina

^[5] Leiden Univ, Med Ctr, Dept Med, Div Endocrinol, NL-2300 RC Leiden - Netherlands

^[6] Univ Extremo Sul Catarinense, BR-88806000 Criciuma, SC - Brazil

^[7] Leiden Univ, Med Ctr, Dept Pediat, NL-2300 RC Leiden - Netherlands

^[8] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 - USA

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 173, n. 3, p. 291-296, SEP 2015.
• Web of Science Citations: 12

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 -1.4 +/- 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 (similar to 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. (AU)

• FAPESP's process: 10/19809-6 - Phenotype related with p.L142fsX161 STAT5B mutation in the heterozygous state
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/15078-0 - Study of the phenotype associated to heterozigous STAT5B mutation p.L142fsX161
• Grantee: Renata da Cunha Scalco Tirapeli
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)