A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study

Yin, Xueling; Wang, Junqi; Han, Tianting; Zhang, Tingting; Li, Yuhong; Dong, Zhiya; Wang, Wei; Li, Chuanyin; Lu, Wenli

doi:10.3389/fgene.2021.663746

Cited by 4 publications

(4 citation statements)

References 20 publications

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“…When similar in vitro ubiquitination reactions were performed with wild-type MKRN3 or mutants (Cys340Arg, Arg365Ser, Phe417Ile, His420Gln) (Figure 2), it was evident that disease-causing mutations in the RING domain or C-terminal region compromised autoubiquitination of MKRN3 (18). These data suggested that CPP-associated MKRN3 mutations may stabilize the MKRN3 protein by altering the activity of E3 ligase (17,18,25). This would lead to a subsequent reduction in autoubiquitination and a slower proteasome-mediated degradation.…”

Section: Ubiquitination and Autoubiquitination Activitymentioning

confidence: 87%

MKRN3 role in regulating pubertal onset: the state of art of functional studies

et al. 2022

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Puberty is a critical process characterized by several physical and psychological changes that culminate in the achievement of sexual maturation and fertility. The onset of puberty depends on several incompletely understood mechanisms that certainly involve gonadotropin-releasing hormone (GnRH) and its effects on the pituitary gland. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP), which to date, represent the most commonly known genetic cause of this condition. The MKRN3 gene showed ubiquitous expression in tissues from a broad spectrum of species, suggesting an important cellular role. Its involvement in the initiation of puberty and endocrine functions has just begun to be studied. This review discusses some of the recent approaches developed to predict MKRN3 functions and its involvement in pubertal development.

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Section: Ubiquitination and Autoubiquitination Activitymentioning

confidence: 87%

MKRN3 role in regulating pubertal onset: the state of art of functional studies

et al. 2022

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“…Since 2013, a total of 50 MKRN3 loss-of-function variants have been reported in the literature [4,[18][19][20][21][22]. There are 2 apparent hot spots.…”

Section: Discussionmentioning

confidence: 99%

Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty

Gernay

Brachet

Boros

et al. 2022

Journal of the Endocrine Society

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Context Idiopathic central precocious puberty (iCPP) is defined by the premature re-activation of the hypothalamic-pituitary-gonadal axis with normal MRI of the central nervous system, causing the development of secondary sexual characteristics prior to the age of 8 years in girls and 9 years in boys. MKRN3 loss of function variants now represent the most common genetic cause of iCPP. Purpose To document the clinical course of puberty in 8 families harboring pathogenic MKRN3 variants. Method This is an observational case series study of patients with CPP due to MKRN3 variants followed in a single center. Results Genetic analysis of MKRN3 was carried out in 28 unrelated patients with iCPP and a family history of paternal inheritance or no/unavailable maternal inheritance, particularly in case of very early and rapidly evolving CPP. We identified six novel and two recently described variants in the MKRN3 gene in 9 girls, one boy and their family members. These mutations were all predicted to be deleterious by in silico prediction programs Conclusion We have identified six novel MKRN3 mutations in children with CPP. An MKRN3 loss of function should be considered after careful history pinpointing paternally inherited CPP. Family segregation study allowed the detection of a MKRN3 variant in two young brothers still prepubertal, raising the question of screening and management of asymptomatic prepubertal family members.

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“…( 16 ) reported four pathogenic variants of MKRN 3 in familial CPP. Variants, including whole gene deletions, have been identified since then in > 100 patients with familial and/or idiopathic CPP, the most frequently identified CPP worldwide ( 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ).…”

Section: Makorin Ring Finger Protein 3 (Mkrn3)mentioning

confidence: 99%

“…2 . These variants include a gene deletion, six promoter region abnormalities, and five nonsense, 13 frameshift, and 31 missense variants ( 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ). In vitro studies have shown that the promoter activity of MKRN3 is reduced in variants with promoter region abnormalities than that in wild-type ( 37 , 40 , 42 ).…”

Section: Makorin Ring Finger Protein 3 (Mkrn3)mentioning

confidence: 99%

Genetic causes of central precocious puberty

Tajima

2022

Clin Pediatr Endocrinol

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. Central precocious puberty (CPP) is a condition in which the hypothalamus–pituitary–gonadal system is activated earlier than the normal developmental stage. The etiology includes organic lesions in the brain; however, in the case of idiopathic diseases, environmental and/or genetic factors are involved in the development of CPP. A genetic abnormality in KISS1R , that encodes the kisspeptin receptor, was first reported in 2008 as a cause of idiopathic CPP. Furthermore, genetic alterations in KISS1 , MKRN3 , DLK1 , and PROKR2 have been reported in idiopathic and/or familial CPP. Of these, MKRN3 has the highest frequency of pathological variants associated with CPP worldwide; but, abnormalities in MKRN3 are rare in patients in East Asia, including Japan. MKRN3 and DLK1 are maternal imprinting genes; thus, CPP develops when a pathological variant is inherited from the father. The mechanism of CPP due to defects in MKRN3 and DLK1 has not been completely clarified, but it is suggested that both may negatively control the progression of puberty. CPP due to such a single gene abnormality is extremely rare, but it is important to understand the mechanisms of puberty and reproduction. A further development in the genetics of CPP is expected in the future.

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A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study

Cited by 4 publications

References 20 publications

MKRN3 role in regulating pubertal onset: the state of art of functional studies

MKRN3 role in regulating pubertal onset: the state of art of functional studies

Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty

Genetic causes of central precocious puberty

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