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Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty

Abstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females a... Full description

Journal Title: The journal of clinical endocrinology and metabolism 2018, Vol.103 (2), p.649-659
Main Author: Howard, Sasha R
Other Authors: Guasti, Leonardo , Poliandri, Ariel , David, Alessia , Cabrera, Claudia P , Barnes, Michael R , Wehkalampi, Karoliina , O’Rahilly, Stephen , Aiken, Catherine E , Coll, Anthony P , Ma, Marcella , Rimmington, Debra , Yeo, Giles S H , Dunkel, Leo
Format: Electronic Article Electronic Article
Language: English
Subjects:
Sex
Publisher: Washington, DC: Endocrine Society
ID: ISSN: 0021-972X
Link: https://www.ncbi.nlm.nih.gov/pubmed/29161441
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5800831
title: Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty
format: Article
creator:
  • Howard, Sasha R
  • Guasti, Leonardo
  • Poliandri, Ariel
  • David, Alessia
  • Cabrera, Claudia P
  • Barnes, Michael R
  • Wehkalampi, Karoliina
  • O’Rahilly, Stephen
  • Aiken, Catherine E
  • Coll, Anthony P
  • Ma, Marcella
  • Rimmington, Debra
  • Yeo, Giles S H
  • Dunkel, Leo
subjects:
  • 1103 Clinical Sciences
  • 1114 Paediatrics And Reproductive Medicine
  • 3121 Internal medicine
  • Adolescent
  • Alpha
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
  • Animals
  • Based Medicine
  • Body fat
  • Body mass
  • Body Mass Index
  • Body Weight
  • Body Weight - genetics
  • Case
  • Case-Control Studies
  • Child
  • Clinical Research Articles
  • Clinical s
  • Control Studies
  • Delayed
  • Demethylation
  • Dependent Dioxygenase FTO
  • Endocrinology & Metabolism
  • Energy balance
  • Female
  • Females
  • Filtration
  • Gene sequencing
  • Genes
  • Genetic factors
  • Genome
  • Genome-wide association studies
  • Genome-Wide Association Study
  • Genomes
  • Humans
  • Ketoglutarate
  • Knockout
  • Linkage disequilibrium
  • Male
  • Males
  • Menarche
  • Mice
  • Mice, Knockout
  • Muridae
  • Mutation
  • Pathogenesis
  • Pathogenicity
  • Pathogens
  • Pedigree
  • Phenotype
  • Phenotypes
  • Polymorphism
  • Polymorphism, Single Nucleotide
  • Puberty
  • Puberty - genetics
  • Puberty, Delayed - genetics
  • Reproductive Biology
  • Sex
  • Single Nucleotide
  • Time Factors
  • Wide Association Study
ispartof: The journal of clinical endocrinology and metabolism, 2018, Vol.103 (2), p.649-659
description: Abstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. We assessed the contribution of rare variants in genes important in the timing of puberty and body mass regulation in the general population to the phenotype of familial delayed puberty.
language: eng
source:
identifier: ISSN: 0021-972X
fulltext: no_fulltext
issn:
  • 0021-972X
  • 1945-7197
url: Link


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titleContributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty
creatorHoward, Sasha R ; Guasti, Leonardo ; Poliandri, Ariel ; David, Alessia ; Cabrera, Claudia P ; Barnes, Michael R ; Wehkalampi, Karoliina ; O’Rahilly, Stephen ; Aiken, Catherine E ; Coll, Anthony P ; Ma, Marcella ; Rimmington, Debra ; Yeo, Giles S H ; Dunkel, Leo
creatorcontribHoward, Sasha R ; Guasti, Leonardo ; Poliandri, Ariel ; David, Alessia ; Cabrera, Claudia P ; Barnes, Michael R ; Wehkalampi, Karoliina ; O’Rahilly, Stephen ; Aiken, Catherine E ; Coll, Anthony P ; Ma, Marcella ; Rimmington, Debra ; Yeo, Giles S H ; Dunkel, Leo
descriptionAbstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. We assessed the contribution of rare variants in genes important in the timing of puberty and body mass regulation in the general population to the phenotype of familial delayed puberty.
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languageeng
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subject1103 Clinical Sciences ; 1114 Paediatrics And Reproductive Medicine ; 3121 Internal medicine ; Adolescent ; Alpha ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics ; Animals ; Based Medicine ; Body fat ; Body mass ; Body Mass Index ; Body Weight ; Body Weight - genetics ; Case ; Case-Control Studies ; Child ; Clinical Research Articles ; Clinical s ; Control Studies ; Delayed ; Demethylation ; Dependent Dioxygenase FTO ; Endocrinology & Metabolism ; Energy balance ; Female ; Females ; Filtration ; Gene sequencing ; Genes ; Genetic factors ; Genome ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Humans ; Ketoglutarate ; Knockout ; Linkage disequilibrium ; Male ; Males ; Menarche ; Mice ; Mice, Knockout ; Muridae ; Mutation ; Pathogenesis ; Pathogenicity ; Pathogens ; Pedigree ; Phenotype ; Phenotypes ; Polymorphism ; Polymorphism, Single Nucleotide ; Puberty ; Puberty - genetics ; Puberty, Delayed - genetics ; Reproductive Biology ; Sex ; Single Nucleotide ; Time Factors ; Wide Association Study
ispartofThe journal of clinical endocrinology and metabolism, 2018, Vol.103 (2), p.649-659
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1Guasti, Leonardo
2Poliandri, Ariel
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7O’Rahilly, Stephen
8Aiken, Catherine E
9Coll, Anthony P
10Ma, Marcella
11Rimmington, Debra
12Yeo, Giles S H
13Dunkel, Leo
title
0Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty
1The journal of clinical endocrinology and metabolism
addtitleJ Clin Endocrinol Metab
descriptionAbstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. We assessed the contribution of rare variants in genes important in the timing of puberty and body mass regulation in the general population to the phenotype of familial delayed puberty.
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01103 Clinical Sciences
11114 Paediatrics And Reproductive Medicine
23121 Internal medicine
3Adolescent
4Alpha
5Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
6Animals
7Based Medicine
8Body fat
9Body mass
10Body Mass Index
11Body Weight
12Body Weight - genetics
13Case
14Case-Control Studies
15Child
16Clinical Research Articles
17Clinical s
18Control Studies
19Delayed
20Demethylation
21Dependent Dioxygenase FTO
22Endocrinology & Metabolism
23Energy balance
24Female
25Females
26Filtration
27Gene sequencing
28Genes
29Genetic factors
30Genome
31Genome-wide association studies
32Genome-Wide Association Study
33Genomes
34Humans
35Ketoglutarate
36Knockout
37Linkage disequilibrium
38Male
39Males
40Menarche
41Mice
42Mice, Knockout
43Muridae
44Mutation
45Pathogenesis
46Pathogenicity
47Pathogens
48Pedigree
49Phenotype
50Phenotypes
51Polymorphism
52Polymorphism, Single Nucleotide
53Puberty
54Puberty - genetics
55Puberty, Delayed - genetics
56Reproductive Biology
57Sex
58Single Nucleotide
59Time Factors
60Wide Association Study
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10Ma, Marcella
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12Yeo, Giles S H
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titleContributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty
authorHoward, Sasha R ; Guasti, Leonardo ; Poliandri, Ariel ; David, Alessia ; Cabrera, Claudia P ; Barnes, Michael R ; Wehkalampi, Karoliina ; O’Rahilly, Stephen ; Aiken, Catherine E ; Coll, Anthony P ; Ma, Marcella ; Rimmington, Debra ; Yeo, Giles S H ; Dunkel, Leo
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11114 Paediatrics And Reproductive Medicine
23121 Internal medicine
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4Alpha
5Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
6Animals
7Based Medicine
8Body fat
9Body mass
10Body Mass Index
11Body Weight
12Body Weight - genetics
13Case
14Case-Control Studies
15Child
16Clinical Research Articles
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18Control Studies
19Delayed
20Demethylation
21Dependent Dioxygenase FTO
22Endocrinology & Metabolism
23Energy balance
24Female
25Females
26Filtration
27Gene sequencing
28Genes
29Genetic factors
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31Genome-wide association studies
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59Time Factors
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abstractAbstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. We assessed the contribution of rare variants in genes important in the timing of puberty and body mass regulation in the general population to the phenotype of familial delayed puberty.
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pmid29161441
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