Although a variety of environmental and biologic factors are known to influence the timing of puberty, genetic background is among the most important modulators. The correlation between the timing of pubertal milestones among children and their parents and between monozygotic twins indicates that 48-80% of the variance in pubertal onset is genetically controlled. Regulation of the timing of puberty is, however, unlikely to exhibit classic Mendelian inheritance or be attributable to a single locus; rather, it is likely to be a complex genetic trait that is modulated by variations in multiple genes. Increasing evidence suggests that the presence of particular common variants or combinations of variants within an individual's genome modulate the expression of complex traits, such as the onset of puberty. It is the broad goal of this proposal to identify the genetic factors that regulate the timing of puberty in humans. The proposal is designed to test the hypothesis that the genetic regulation of puberty is polygenic and derives from the effects of common sequence variants. This question will be addressed by: 1) generating a DNA collection from subjects whose pubertal onset occurred extremely early or extremely late and including parental DNA in the collection so that informative association studies can be performed; 2) determining whether the known polymorphisms in the genes for leptin and/or its receptor associate with specific patterns of pubertal onset; 3) extending the analysis to other genes known to modulate hypothalamic-pituitary-gonadal (HPG) function by employing high-throughput screening techniques to identify specific allelic variations that associate with diverse patterns of pubertal onset; and 4) defining the genotype/phenotype correlations across the spectrum from precocious to delayed puberty for those allelic variants that are shown to associate with specific patterns of pubertal onset. Identification of genes that regulate the timing of puberty will greatly enhance the understanding of the HPG axis and will provide insight into abnormal patterns of growth and development, such as central precocious puberty and delayed puberty.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR015544-06
Application #
6773291
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2000-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$125,820
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Zhu, Jia; Choa, Ruth E-Y; Guo, Michael H et al. (2015) A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 100:E646-54
Nathan, Brandon M; Hodges, Craig A; Supelak, Pamela J et al. (2006) A quantitative trait locus on chromosome 6 regulates the onset of puberty in mice. Endocrinology 147:5132-8
Banerjee, Indraneel; Trueman, Julie A; Hall, Catherine M et al. (2006) Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms. Eur J Endocrinol 155:121-6
Nathan, Brandon M; Sedlmeyer, Ines L; Palmert, Mark R (2006) Impact of body mass index on growth in boys with delayed puberty. J Pediatr Endocrinol Metab 19:971-7
Jin, R; Hodges, C A; Drumm, M L et al. (2006) The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice. J Med Genet 43:e29
Sedlmeyer, Ines L; Pearce, Celeste Leigh; Trueman, Julie A et al. (2005) Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing. J Clin Endocrinol Metab 90:1091-9
Palmert, Mark R; Alexander, Sarah W; Goorin, Allen M (2004) Ovarian toxicity after chemotherapy: possible association with ifosfamide administration. Pediatr Blood Cancer 42:216-9
Krewson, Thomas D; Supelak, Pamela J; Hill, Annie E et al. (2004) Chromosomes 6 and 13 harbor genes that regulate pubertal timing in mouse chromosome substitution strains. Endocrinology 145:4447-51
Palmert, Mark R; Hirschhorn, Joel N (2003) Genetic approaches to stature, pubertal timing, and other complex traits. Mol Genet Metab 80:1-10
Sedlmeyer, Ines L; Hirschhorn, Joel N; Palmert, Mark R (2002) Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. J Clin Endocrinol Metab 87:5581-6

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