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

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 7; pp. 3491 - 3496
• Main Authors: Trarbach, Ericka B., Abreu, Ana Paula, Silveira, Leticia Ferreira Gontijo, Garmes, Heraldo Mendes, Baptista, Maria Tereza M., Teles, Milena Gurgel, Costa, Elaine M. F., Mohammadi, Moosa, Pitteloud, Nelly, Mendonca, Berenice B., Latronico, Ana Claudia
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.07.2010; Copyright by The Endocrine Society; The Endocrine Society
• Subjects: Biological and medical sciences; Codon, Nonsense - genetics; Endocrinopathies; Feeding. Feeding behavior; Fibroblast Growth Factor 8 - genetics; Follicle Stimulating Hormone - blood; Fundamental and applied biological sciences. Psychology; Humans; Hypogonadism - genetics; Luteinizing Hormone - blood; Male; Medical sciences; Original; Radioimmunoassay; Severity of Illness Index; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Human; Obesity; Gene; Nutrition; Nonsense mutation; Deficiency; Nutrition disorder; Genetics; Metabolic diseases; Gonadotropin; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2010-0176

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. Two novel nonsense FGF8 gene mutations were identified in two families with isolated hypogonadotropic hypogonadism, confirming that its loss-of-function causes human GnRH deficiency.