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

Abstract

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 0 CTTT repeat) and LR polymorphisms (GlnOArg 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. 155 121-126 European Journal of Endocrinology

Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene

“…Previously, we reported the results of screening a group of CDGP children for known polymorphisms within LEP and screening for novel LEP sequence variants in a small subset of this group (nZ30). The known polymorphisms were not associated with CDGP, but homozygosity for the 3 0 CTTT short repeat was associated with an increased BMI SDS in this CDGP group (9). We now report the identification of a novel missense sequence variant within LEP found by screening the whole group of children with CDGP for novel variants within the LEP gene, and describe investigations to define its function.…”

“…Children with CDGP have reduced body mass index (BMI) compared with control subjects (9). A number of families with CDGP show a dominant pattern of inheritance and estimates of the heritability of CDGP suggest 50-80% of the variance in pubertal onset may be genetically controlled (10).…”

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

“…CDGP appears to be a multifactorial trait, yet at the same time the inheritance patterns suggests that single genes exert major effects (30). Although previous studies failed to identify mutations in candidate genes in patients with CDGP (33)(34)(35)(36)(37)(38), the GHSR gene has not been previously investigated in patients with this condition (7)(8)(9). We regard our findings as hypothesis generating; it will be of great interest to screen other clinical cohorts with CDGP (as well as family members) to determine the frequency and inheritance pattern of GHSR mutations in various populations.…”

Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene.

“…Of the single genes investigated for association with CDGP, polymorphic markers in the genes for GnRH and GnRH-R show only weak association (3). Common polymorphisms in the leptin and leptin receptor genes are not associated with CDGP, although a specific leptin genotype does influence the CDGP phenotype; homozygotes for the long allele for the CT repeat in the 3 0 UTR have a greater body mass index (BMI) SDS than heterozygotes or short allele homozygotes (4). Furthermore, there is no association between a polymorphic adenine deletion in the cocaine and amphetamine-regulated transcript (CART) gene, which modulates the action of leptin on GnRH secretion and CDGP (PE Clayton, unpublished observations).…”