Nonsense Mutations in FGF8 Gene Causing Different Degrees of Human Gonadotropin-Releasing Deficiency

Autor(es):Mostrar menos -

Trarbach, Ericka B. ^[1] ; Abreu, Ana Paula ^[1] ; Gontijo Silveira, Leticia Ferreira ^[1] ; Garmes, Heraldo Mendes ^[2] ; Baptista, Maria Tereza M. ^[2] ; Teles, Milena Gurgel ^[1] ; Costa, Elaine M. F. ^[1] ; Mohammadi, Moosa ^[3] ; Pitteloud, Nelly ^{[4, 5]} ; Mendonca, Berenice B. ^[1] ; Latronico, Ana Claudia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Disciplina Endocrinol, Hosp Clin, Lab Hormonios & Genet Mol LIM42, Unidade Endocrinol Desenvolvimento, Fac Med, BR-05403900 Sao Paulo - Brazil

^[2] Univ Estadual Campinas, Fac Med, Dept Clin Med, Disciplina Endocrinol, BR-13083000 Campinas, SP - Brazil

^[3] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 - USA

^[4] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 - USA

^[5] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 95, n. 7, p. 3491-3496, JUL 2010.
• Citações Web of Science: 44

Resumo

Context: FGFR1 mutations cause isolated hypogonadotropic hypogonadism (IHH) with or without olfactory abnormalities, Kallmann syndrome, and normosmic IHH respectively. Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor receptor (FGFR) 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency. Objective: Our objective was to analyze the clinical, hormonal, and molecular findings of two familial IHH patients due to FGF8 gene mutations. Methods and Patients: The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives. Results: Two unique heterozygous nonsense mutations in FGF8(p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency. Conclusions: We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency. (J Clin Endocrinol Metab 95: 3491-3496, 2010) (AU)

• Processo FAPESP: 07/50938-4 - Determinação da base molecular do hipogonadotrófico isolado congênito
• Beneficiário: Ericka Barbosa Trarbach
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático