Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study

Background: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective: Our aim was to investigate genetic and biochemical a...

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Detalhes bibliográficos
Autores: Montenegro, L, Labarta, JI, Piovesan, M, Canton, APM, Corripio, R, Soriano-Guillen, L, Travieso-Suarez, L, Martin-Rivada, A, Barrios, V, Seraphim, CE, Brito, VN, Latronico, AC, Argente, J
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2020
País:España
Recursos:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositório:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p2467
Acesso em linha:https://i3pt.portalinvestigacion.com/publicaciones/2467
Access Level:Acceso aberto
Palavra-chave:precocious puberty
DLK1
genetics
mutations
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repository_id_str
spelling Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish StudyMontenegro, LLabarta, JIPiovesan, MCanton, APMCorripio, RSoriano-Guillen, LTravieso-Suarez, LMartin-Rivada, ABarrios, VSeraphim, CEBrito, VNLatronico, ACArgente, Jprecocious pubertyDLK1geneticsmutationsBackground: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective: Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients: A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results: Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels. Conclusion: Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.ENDOCRINE SOC2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://i3pt.portalinvestigacion.com/publicaciones/2467JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISMISSN: 0021972XISSNe: 19457197reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulíinstname:Institut d'Investigació i Innovació Parc Taulí (I3PT)Inglésinfo:eu-repo/semantics/openAccessoai:i3pt.fundanetsuite.com:p24672026-06-21T15:30:37Z
dc.title.none.fl_str_mv Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
title Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
spellingShingle Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
Montenegro, L
precocious puberty
DLK1
genetics
mutations
title_short Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
title_full Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
title_fullStr Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
title_full_unstemmed Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
title_sort Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study
dc.creator.none.fl_str_mv Montenegro, L
Labarta, JI
Piovesan, M
Canton, APM
Corripio, R
Soriano-Guillen, L
Travieso-Suarez, L
Martin-Rivada, A
Barrios, V
Seraphim, CE
Brito, VN
Latronico, AC
Argente, J
author Montenegro, L
author_facet Montenegro, L
Labarta, JI
Piovesan, M
Canton, APM
Corripio, R
Soriano-Guillen, L
Travieso-Suarez, L
Martin-Rivada, A
Barrios, V
Seraphim, CE
Brito, VN
Latronico, AC
Argente, J
author_role author
author2 Labarta, JI
Piovesan, M
Canton, APM
Corripio, R
Soriano-Guillen, L
Travieso-Suarez, L
Martin-Rivada, A
Barrios, V
Seraphim, CE
Brito, VN
Latronico, AC
Argente, J
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv precocious puberty
DLK1
genetics
mutations
topic precocious puberty
DLK1
genetics
mutations
description Background: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective: Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients: A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results: Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels. Conclusion: Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://i3pt.portalinvestigacion.com/publicaciones/2467
url https://i3pt.portalinvestigacion.com/publicaciones/2467
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ENDOCRINE SOC
publisher.none.fl_str_mv ENDOCRINE SOC
dc.source.none.fl_str_mv JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
ISSN: 0021972X
ISSNe: 19457197
reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
instname:Institut d'Investigació i Innovació Parc Taulí (I3PT)
instname_str Institut d'Investigació i Innovació Parc Taulí (I3PT)
reponame_str r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
collection r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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