title: STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability.
abstract: 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 (∼ 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.
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Renata C
authors.initials: RC
authors.lastname: Scalco
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Horacio M
authors.initials: HM
authors.lastname: Domené
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Jasper
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Belgorosky
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Marino
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pereira
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Tonelli
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.affiliation: Unidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Arnaldo, 455 5° Andar Sala 5340, 01246-903 Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyCincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USACentro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE)CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, ArgentinaEndocrine ServiceHospital de Pediatria Garrahan, Ciudad Autonoma de Buenos Aires Pozos 1881, 1245 Buenos Aires, ArgentinaDivision of EndocrinologyDepartment of Medicine, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsUniversidade do Extremo Sul Catarinense88806-000 Criciúma, Santa Catarina, BrazilDepartment of PediatricsLeiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of PediatricsOregon Health and Science University, Portland, Oregon 97239, USA alexj@usp.br alexj@pq.cnpq.br.
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D000293:Adolescent; D000328:Adult; D001827:Body Height / Q000235:genetics*; D002648:Child; D004485:Eczema / Q000209:etiology / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D046150:Laron Syndrome / Q000150:complications / Q000235:genetics*; D017563:Lung Diseases, Interstitial / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D050799:STAT5 Transcription Factor / Q000235:genetics*; D055815:Young Adult
chemical_list: D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human