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MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations

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Abstract

Purpose

MKNR3 is a paternally expressed gene whose mutations are the main cause of central precocious puberty (CPP). Protein circulating levels can be easily measured, as demonstrated in idiopathic CPP and healthy controls. No data are available for patients harboring an MKRN3 mutation. Our aim was to perform MKRN3 mutation screening and to investigate if circulating protein levels could be a screening tool to identify MKRN3 mutation in CPP patients.

Methods

We enrolled 140 CPP girls and performed MKRN3 mutation analysis. Patients were stratified into two groups: idiopathic CPP (iCPP) and MKRN3 mutation-related CPP (MKRN3-CPP). Clinical characteristics were collected. Serum MKRN3 values were measured by a commercially available ELISA assay kit in MKRN3-CPP and a subgroup of 15 iCPP patients.

Results

We identified 5 patients with MKRN3 mutations: one was a novel mutation (p.Gln352Arg) while the others were previously reported (p.Arg328Cys, p.Arg345Cys, p.Pro160Cysfs*14, p.Cys410Ter). There was a significant difference in circulating MKRN3 values in MKRN3-CPP compared to iCPP (p < 0.001). In MKRN3-CPP, the subject harboring Pro160Cysfs*14 presented undetectable levels. Subjects carrying the missense mutations p.Arg328Cys and p.Gln352Arg showed divergent circulating protein levels, respectively 40.56 pg/mL and undetectable. The patient with the non-sense mutation reported low but measurable MKRN3 levels (12.72 pg/mL).

Conclusions

MKRN3 defect in patients with CPP cannot be predicted by MKRN3 circulating levels, although those patients presented lower protein levels than iCPP. Due to the great inter-individual variability of the assay and the lack of reference values, no precise cut-off can be identified to suspect MKRN3 defect.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We gratefully thank all the patients, family members, and staff from all the units that participated in the study. We thank all members of the Italian Society for Pediatric Endocrinology and Diabetology (SIEDP) study group on growth and pubertal development for supporting the study. A special thanks to all the Italian Medical Center who participated in enrolling the patients, below the list: Endocrinological Unit of AOU “Federico II”, Naples; Clinic of Pediatrics, University of Chieti, Chieti; Pediatric Unit, University of Modena and Reggio Emilia, Modena; Endocrinological Unit, Department of Pediatrics, Pediatric Hospital Giovanni XXIII, University of Bari, Bari; Unit of Pediatrics, Department of Medicine and Surgery, University of Parma, Parma; Department of Pediatric Endocrinology, Unit of Pediatrics, Department of Medical & Surgical Sciences, University of Bologna, Bologna; Medical Genetic and Endocrinology of Cesena, AUSL Romagna, Pediatric Endocrinology unit, Department of Pediatrics, "Carlo Poma" Hospital, Mantova; Endocrinology Unit, Pediatric University Department, Bambino Gesù Children's Hospital, Rome; Pediatric Endocrinology Unit, Department of Pediatrics, Santobono-Pausilipon Children's Hospital, Pediatric Unit, University of Modena and Reggio Emilia, Modena, Italy.

Funding

This work was supported by a grant (390) funded by “VALERE: VAnviteLli pEr la RicErca” program of University of Campania “L. Vanvitelli”.

Author information

Authors and Affiliations

  1. Department of Women’s and Children’s Health and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 2, 80138, Napoli, Italy

    F. Aiello, S. Palumbo, G. Cirillo, C. Luongo, A. Festa, E. Miraglia del Giudice & A. Grandone

  2. Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy

    G. Tornese

  3. Pediatric Endocrinology Unit, Department of Pediatrics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy

    D. Fava

  4. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16147, Genoa, Italy

    D. Fava

  5. Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

    M. Wasniewska

  6. Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, Bari, Italy

    M. F. Faienza

  7. Unit of Endocrinology and Rare Endocrine Diseases, Giovanni XXIII Pediatric Hospital, Bari, Italy

    M. F. Faienza

  8. Pediatric and Adolescent Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy

    M. Bozzola

  9. Onlus, Il Bambino e Il Suo Pediatra, Novara, Galliate, Italy

    M. Bozzola

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  1. F. Aiello
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  2. S. Palumbo
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  3. G. Cirillo
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  5. D. Fava
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  9. C. Luongo
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  11. E. Miraglia del Giudice
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Contributions

AG conceived the study idea and supervised the work process. AG, SP and GC elaborated the design. Recruitment and clinical management were performed by GT, DF, MW, MFF, CL, AF, EMG. Genetic analysis was performed by SP and GC. FA reviewed the literature, collected the data, wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript. FA prepared the drafts for publication. All authors read and approved the final manuscript.

Corresponding author

Correspondence to S. Palumbo.

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The authors have no competing interests to declare that are relevant to the content of this article.

Ethical approval

This study involved human participants, their data and biological material. Approval was obtained from the ethics committee of University “Luigi Vanvitelli”, Naples, Italy. The procedures used in this study adhere to the tenets of the 1964 Declaration of Helsinki  and its later amendments.

Research involving human participants and/or animals

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Written informed consent was obtained from all parents of individual participants included in the study. An oral assent was obtained by the patients themselves.

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Aiello, F., Palumbo, S., Cirillo, G. et al. MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations. J Endocrinol Invest (2023). https://doi.org/10.1007/s40618-023-02255-5

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