Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms.

OBJECTIVES Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed whether a) L or LR gene polymorphisms were associated with CDGP and b) the CDGP phenotype was influenced by these polymorphisms. DESIGN Case-control and transmission disequilibrium tests were used to test genetic association of L and LR polymorphisms with CDGP. METHODS We genotyped L (3'CTTT repeat) and LR polymorphisms (Gln > Arg substitution, exon 6) in 81 CDGP children and 94 controls in the UK and 88 CDGP children from the US and assessed the effect of genotype on their anthropometric characteristics. RESULTS There was no association of these L or LR gene polymorphisms with CDGP. There was no difference in height or bone age delay within L or LR genotypes. However, UK CDGP children homozygous for the L short allele were heavier than heterozygotes and long allele homozygotes, with a similar trend in the US cohort. UK CDGP children with severe pubertal delay, who were thin, had significantly greater bone age delay and an increased frequency of parental pubertal delay than other groups and were less likely to be L short allele homozygotes. CONCLUSIONS There was no association of specific L or LR polymorphisms with CDGP, but L short allele carriage influenced the phenotype within CDGP.

[1]  M. Palmert,et al.  Delayed puberty: analysis of a large case series from an academic center. , 2002, The Journal of clinical endocrinology and metabolism.

[2]  V. Tillmann,et al.  Serum leptin through childhood and adolescence , 1997, Clinical endocrinology.

[3]  D. McKechnie,et al.  Repeat unit multipriming and hybridisation--a novel method for the production of DNA fingerprints using minisatellite probes. , 1991, Nucleic acids research.

[4]  T J Cole,et al.  Body mass index reference curves for the UK, 1990. , 1995, Archives of disease in childhood.

[5]  T J Cole,et al.  Cross sectional stature and weight reference curves for the UK, 1990. , 1995, Archives of disease in childhood.

[6]  K. Mounzih,et al.  Leptin treatment rescues the sterility of genetically obese ob/ob males. , 1997, Endocrinology.

[7]  D Curtis,et al.  A note on the application of the transmission disequilibrium test when a parent is missing. , 1995, American journal of human genetics.

[8]  W. Chung,et al.  Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity. , 1997, Biochemical and biophysical research communications.

[9]  R. Leibel,et al.  Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study , 1999, International Journal of Obesity.

[10]  R. Considine,et al.  Serum immunoreactive-leptin concentrations in normal-weight and obese humans. , 1996, The New England journal of medicine.

[11]  K. Clément,et al.  A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction , 1998, Nature.

[12]  R. Leibel,et al.  Leptin: A Molecule Integrating Somatic Energy Stores, Energy Expenditure and Fertility , 1998, Trends in Endocrinology & Metabolism.

[13]  T. Ogihara,et al.  A novel microsatellite polymorphism in the human OB gene: a highly polymorphic marker for linkage analysis , 1996, Diabetologia.

[14]  O. Pedersen,et al.  A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference , 2002, International Journal of Obesity.

[15]  A F Roche,et al.  CDC growth charts: United States. , 2000, Advance data.

[16]  P. McKeigue,et al.  Leptin receptor gene variation and obesity: lack of association in a white British male population. , 1997, Human molecular genetics.

[17]  L. Tartaglia,et al.  Phenotypes of Mouse diabetes and Rat fatty Due to Mutations in the OB (Leptin) Receptor , 1996, Science.

[18]  R. Steiner,et al.  Leptin is a metabolic gate for the onset of puberty in the female rat. , 1997, Endocrinology.

[19]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[20]  F. Chehab,et al.  Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin , 1996, Nature Genetics.

[21]  V. Tillmann,et al.  Constitutional delay in growth and puberty (CDGP) is associated with hypoleptinaemia , 1999, Clinical endocrinology.

[22]  J. Hirschhorn,et al.  Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. , 2002, The Journal of clinical endocrinology and metabolism.

[23]  A. Strosberg,et al.  A leptin missense mutation associated with hypogonadism and morbid obesity , 1998, Nature Genetics.

[24]  Hongping,et al.  Leptin is a metabolic signal to the reproductive system. , 1996, Endocrinology.

[25]  J. Hirschhorn,et al.  Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing. , 2005, The Journal of clinical endocrinology and metabolism.