Tero Varimo1, Anna-Pauliina Iivonen2, Marek Niedziela3, Taneli Raivio4,5, Johanna Känsäkoski2, Karoliina Wehkalampi1, Matti Hero1, Kirsi Vaaralahti2, Päivi J Miettinen1. 1. New Children's Hospital, Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland. 2. Stem Cells and Metabolism Research Program, Research Program Unit, University of Helsinki, Helsinki, Finland. 3. Department of Pediatric Endocrinology and Rheumatology, Karol Jonscher's Clinical Hospital, Poznan University of Medical Sciences, Poznan, Poland. 4. New Children's Hospital, Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland. taneli.raivio@helsinki.fi. 5. Stem Cells and Metabolism Research Program, Research Program Unit, University of Helsinki, Helsinki, Finland. taneli.raivio@helsinki.fi.
Abstract
BACKGROUND: Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families. METHODS: The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment. RESULTS: A paternally inherited novel heterozygous c.939C>G, p.(Ile313Met) missense mutation affecting the RING finger domain of MKRN3 was found in a Finnish girl with CPP (age at presentation 6 years). Two Polish siblings (a girl presenting with B2 at the age of 4 years and a boy with adult size testes at the age of 9 years) had inherited a novel heterozygous MKRN3 mutation c.1237_1252delGGAGACACATGCTTTT p.(Gly413Thrfs*63) from their father. The girls were treated with GnRH analogs, which exhibited suppression of the hypothalamic-pituitary-gonadal axis. In contrast, the male patient was not treated, yet he reached his target height. CONCLUSIONS: We describe two novel MKRN3 mutations in three CPP patients. The first long-term data on a boy with CPP due to an MKRN3 mutation questions the role of GnRH analog treatment in augmenting adult height in males with this condition. IMPACT: We describe the genetic cause for central precocious puberty (CPP) in two families. This report adds two novel MKRN3 mutations to the existing literature. One of the mutations, p.(Ile313Met) affects the RING finger domain of MKRN3, which has been shown to be important for repressing the promoter activity of KISS1 and TAC3. We describe the first long-term observation of a male patient with CPP due to a paternally inherited MKRN3 loss-of-function mutation. Without GnRH analog treatment, he achieved an adult height that was in accordance with his mid-parental target height.
BACKGROUND: Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families. METHODS: The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment. RESULTS: A paternally inherited novel heterozygous c.939C>G, p.(Ile313Met) missense mutation affecting the RING finger domain of MKRN3 was found in a Finnish girl with CPP (age at presentation 6 years). Two Polish siblings (a girl presenting with B2 at the age of 4 years and a boy with adult size testes at the age of 9 years) had inherited a novel heterozygous MKRN3 mutation c.1237_1252delGGAGACACATGCTTTT p.(Gly413Thrfs*63) from their father. The girls were treated with GnRH analogs, which exhibited suppression of the hypothalamic-pituitary-gonadal axis. In contrast, the male patient was not treated, yet he reached his target height. CONCLUSIONS: We describe two novel MKRN3 mutations in three CPP patients. The first long-term data on a boy with CPP due to an MKRN3 mutation questions the role of GnRH analog treatment in augmenting adult height in males with this condition. IMPACT: We describe the genetic cause for central precocious puberty (CPP) in two families. This report adds two novel MKRN3 mutations to the existing literature. One of the mutations, p.(Ile313Met) affects the RING finger domain of MKRN3, which has been shown to be important for repressing the promoter activity of KISS1 and TAC3. We describe the first long-term observation of a male patient with CPP due to a paternally inherited MKRN3 loss-of-function mutation. Without GnRH analog treatment, he achieved an adult height that was in accordance with his mid-parental target height.
Authors: H S Lee; H-S Jin; Y S Shim; H R Jeong; E Kwon; V Choi; M-C Kim; I-S Chung; S-Y Jeong; J S Hwang Journal: Horm Metab Res Date: 2015-05-04 Impact factor: 2.936
Authors: Ana Paula Abreu; Carlos A Toro; Yong Bhum Song; Victor M Navarro; Martha A Bosch; Aysegul Eren; Joy N Liang; Rona S Carroll; Ana Claudia Latronico; Oline K Rønnekleiv; Carlos F Aylwin; Alejandro Lomniczi; Sergio Ojeda; Ursula B Kaiser Journal: J Clin Invest Date: 2020-08-03 Impact factor: 14.808