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

Author(s):Show less -

Montenegro, Luciana ^[1] ; Labarta, I, Jose ; Piovesan, Maira ^[1] ; Canton, Ana P. M. ^[1] ; Corripio, Raquel ^[2] ; Soriano-Guillen, Leandro ^[3] ; Travieso-Suarez, Lourdes ^{[4, 5]} ; Martin-Rivada, Alvaro ^{[4, 5]} ; Barrios, Vicente ^{[4, 5]} ; Seraphim, Carlos E. ^[1] ; Brito, Vinicius N. ^[1] ; Latronico, Ana Claudia ^[1] ; Argente, Jesus ^{[4, 5]}

Affiliation

^[1] Univ Sao Paulo, Disciplina Endocrinol & Metabol, Fac Med, Hosp Clin, Unidade Endocrinol Desenvolvimento, Lab Hormonios, Sao Paulo - Brazil

^[2] Univ Autonoma Barcelona, Pediat Endocrinol Dept, Corporacio Parc Tauli Hosp Univ, Inst Invest & Innovacio Parc Tauli I3PT, Sabadell - Spain

^[3] Univ Autonoma Madrid, Inst Biomed Res, Pediat Endocrinol Unit, Hosp Univ Fdn Jimenez Diaz, Madrid - Spain

^[4] Univ Autonoma Madrid, Ctr Invest Biorned Red Fisiopatol Obesidad & Nutr, Dept Pediat, Inst Salud Carlos III, IMDEA Food Inst, Hosp Infantil Univ Nino Jesus, Inst Invest Princes, Madrid - Spain

^[5] Univ Autonoma Madrid, Ctr Invest Biorned Red Fisiopatol Obesidad & Nutr, Dept Pediat Endocrinol, Inst Salud Carlos III, IMDE, Hosp Infantil Univ Nino Jesus, Inst Invest Princes, Madrid - Spain

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 105, n. 10 OCT 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 17/23892-5 - Analysis of MKRN3 gene in patients with central precocious puberty
• Grantee: Maiara Ribeiro Piovesan
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants