Kallmann Syndrome: Somatic and Germline Mutations of the Fibroblast Growth Factor Receptor 1 Gene in a Mother and the Son

• Published in: The journal of clinical endocrinology and metabolism Vol. 91; no. 4; pp. 1415 - 1418
• Main Authors: Sato, Naoko, Ohyama, Kenji, Fukami, Maki, Okada, Michiyo, Ogata, Tsutomu
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.04.2006; Endocrine Society
• Subjects: Adolescent; Adult; Alleles; Biological and medical sciences; Cleft lip/palate; Deoxyribonucleic acid; DNA; DNA - genetics; DNA sequencing; Endocrinopathies; Female; Fibroblast growth factor receptor 1; Fibroblasts; Frameshift Mutation; Fundamental and applied biological sciences. Psychology; Gene deletion; Genomics; Growth factors; Humans; Hypogonadism; Hypothalamus. Hypophysis. Epiphysis (diseases); Kallmann Syndrome - genetics; Kallmann Syndrome - pathology; Kallmann's syndrome; Leukocytes; Male; Medical sciences; Mosaicism; Mutation; Mutation - physiology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Olfaction; Polymerase chain reaction; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA; Sexual Maturation - genetics; Vertebrates: endocrinology; Endocrinopathy; Hypogonadotropic hypogonadism; Nervous system diseases; Hypothalamic diseases; Kallmann syndrome; Genital diseases; Cerebral disorder; Genetic disease; Somatic mutation; Gene; Mother; Malformation; Germ line; Central nervous system disease; ENT disease; Genetics; Fibroblast growth factor receptor 1; Endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-2266

Context: Although Kallmann syndrome (KS) caused by heterozygous loss of function mutations of the fibroblast growth factor receptor 1 gene (FGFR1) is occasionally associated with characteristic features, such as dental agenesis and cleft palate, FGFR1 mutations remain unidentified in several KS patients with such characteristic features. Subjects and Methods: We examined a 14-yr-old Japanese boy with hypogonadotropic hypogonadism, olfactory dysfunction, and dental agenesis and his fertile mother with olfactory dysfunction and dental agenesis. Direct sequencing was performed for FGFR1 using leukocyte genomic DNA from the proband and leukocyte and nail genomic DNA from the mother. To examine a possible somatic mutation, a specific forward primer was designed to introduce a BstXI site into the normal allele only, and nested PCR amplification, followed by BstXI digestion, was carried out three times with different reverse primers. Results: After standard PCR amplifications, a heterozygous 2-bp deletion at exon 10 (1317_1318delTG), which is predicted to cause a frameshift at the 439th codon for serine and resultant termination at the 461st codon (S439fsX461), was identified in the proband, but was not found in the mother. After selective amplification of the mutant allele, this deletion was detected in nail DNA, but not in leukocyte DNA, from the mother. Conclusion: The results suggest that the 2-bp deletion took place as a somatic mutation in the mother and was transmitted to the boy because of germline mosaicism. Such a somatic mutation occurs in some apparently FGFR1 mutation-negative KS patients with dental agenesis.