title: FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.
abstract: The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA fernandacorrea@usp.br.
authors.forename: Fernanda A
authors.initials: FA
authors.lastname: Correa
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ericka B
authors.initials: EB
authors.lastname: Trarbach
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Cintia
authors.initials: C
authors.lastname: Tusset
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Montenegro
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Luciani R
authors.initials: LR
authors.lastname: Carvalho
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Marcela M
authors.initials: MM
authors.lastname: Franca
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Aline P
authors.initials: AP
authors.lastname: Otto
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Everlayny F
authors.initials: EF
authors.lastname: Costalonga
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Vinicius N
authors.initials: VN
authors.lastname: Brito
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mirian Y
authors.initials: MY
authors.lastname: Nishi
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yisrael
authors.initials: Y
authors.lastname: Sidis
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.affiliation: Unidade de Endocrinologia do DesenvolvimentoLaboratório de Hormônios e Genética Molecular LIM42Unidade de Endocrinologia GenéticaLaboratório de Endocrinologia Celular e Molecular LIM25, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255, 05403-000 São Paulo, BrazilCentre Hospitalier Universitaire Vaudois (CHUV)Faculté de Biologie et Médecine de l'Univesité de Lausanne, Lausanne, SwitzerlandDivision of EndocrinologyDiabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
keywords: FGFR1; PROKR2; combined pituitary hormone deficiencies; hypopituitarism