|
|
Hypogonadotropic Hypogonadism - Mutations and Phenotypes« Back to Volume 23, Issue 3, November 2007 - Table of Contents Isolated hypogonadotropic hypogonadism (IHH) has been associated with mutations in 7 genes to date (Table). The products of the genes encoded by KAL1, FGFR1, PROK2, PROKR2, and NELF assist in the regulation of neural movement within the CNS – particularly the migration of olfactory and gonadotropin releasing hormone (GnRH)-containing neurons from the olfactory placode during early embryogenesis. Mutations in these genes result in abnormalities of GnRH secretion and the reproductive endocrine system (delayed adolescence, hypogonadotropism) and the sense of smell (hyposmia, anosmia), and those afflicted often display other neurologic (bimanual synkinesia) and somatic (renal agenesis) anomalies. These traits are transmitted in an autosomal dominant manner often with incomplete penetrance and substantial inter- and intrafamilial variability in clinical manifestations. Mutations of GPR54 limit release of GnRH while those of the gonadotropin-releasing hormone receptor (GNRHR) impair its function at the gonadotroph membrane. These disorders are transmitted in an autosomal recessive manner and are not associated with other specific clinical or anatomic abnormalities.
Intrigued by the variable clinical manifestations of IHH, Pitteloud and colleagues examined the genotype of 2 families in which single gene defects thought to have resulted in IHH had been previously identified. In pedigree #1, a 21-year old male with IHH and hyposmia was initially found to have a heterozygous mutation in FGFR1 (Ser342Leu - chromosome 8p11.2-p11.1); the proband’s father and sister had the same FGFR1 mutation; the father had delayed onset and the sister normal timing of puberty. In vitro studies demonstrated that the Ser342Leu mutant of FGFR1 acted in a dominant-negative manner. A heterozygous 8 bp deletion in the negative elongation factor (NELF) resulting in a truncated product was later identified in the proband, his mother and his brother; the latter 2 subjects underwent normal puberty. The authors suggested that loss of a single copy of FGFR1 resulted in a less severe phenotype than did loss of a single copy (allele) of both FGFR1 and NELF. In pedigree #2, two sisters with IHH (no evident spontaneous ovarian function) were found to have inactivating mutations in both GNRHR alleles (Gln106Arg, Arg262Gln - chromosome 4q21.2) ie, the sisters had compound heterozygosity. Their father had a history of delayed puberty and carried the Arg262Ser mutation, while their normal mother carried the Gln106Arg mutation. Further studies revealed that the sisters also had a loss-of-function heterozygous mutation in FGFR1 (Leu470Arg), an allele that they had inherited each from their father. Thus, these sisters with a severe IHH phenotype were triallelic for this trait. Why the father who was heterozygous for mutations in both GNRHR and FGFR1 manifested only delayed puberty is uncertain. The investigators concluded that disorders thought to be monogenic in origin and that manifest variable degrees of clinical involvement may actually be oligogenic due to the involvement of 2 (possibly even more) different genes whose mutations sum to produce the clinical phenotype. Pitteloud N, Quinton R, Pearce S, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007;117:457-63. Editor’s CommentA gene mutation has been found in only 30% of patients with IHH. Other genes that regulate migration of GnRH neurons and synthesis and release of or response to GnRH await identification. Clearly the concept of digenic inheritance of disease is one that may well be applicable to many disorders of the endocrine and other systems. Allen W. Root, MD
« Back to Volume 23, Issue 3, November 2007 - Table of Contents
|
Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
