A novel heterozygous MKRN3 nonsense mutation in a Chinese girl with idiopathic central precocious puberty

Liu, Meijuan; Fan, Lijun; Gong, Chun

doi:10.1097/md.0000000000022295

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…The c.841C>T mutation is located in the CH motif and results in a single amino acid change in the MKRN3 protein. Thus far, 50 MKRN3 mutations associated with CPP have been reported, including 14 frameshift mutations, 27 missense mutations, 4 nonsense mutations and 5 variants in upstream promoter or regulatory regions[ 3 , 5 ]. The current case is only the second report of the c.841C>T mutation in MKRN3 [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, this is also the first case of MKRN3 mutation in twin sisters. It is worth noting that mutations in MKRN3 are more common in patients from Western countries than in those from Asian countries[ 3 ], which may result from genetic differences in ethnic groups or the less frequent use of gene testing among children with CPP in Asian countries.…”

Section: Discussionmentioning

confidence: 99%

“…Boys with CPP are more likely to have specific pathological factors, such as thalamic hamartoma. In contrast, 90% of cases of CPP in girls are idiopathic[ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports

Jiang¹,

YanQiong²,

Yuan³

et al. 2021

WJCC

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BACKGROUND Caused by premature activation of the hypothalamic-pituitary-gonadal axis, there is increasing incidence of central precocious puberty (CPP), especially in girls. Makorin ring finger protein 3 ( MKRN3 ), a maternal imprinted gene with a highly conserved sequence, is the most common genetic etiology associated with CPP. Approximately 50 different mutations in MKRN3 have been found in CPP. CASE SUMMARY This case report involves identical twin sisters presenting with premature thelarche at the age of 6 years. The left hand bone age of both patients revealed advanced age (9 years). Pelvic B ultrasound indicated enlargement of the ovaries. Luteinizing hormone (LH) releasing hormone testing confirmed CPP. Whole-exome sequencing detected the c.841C>T mutation in MKRN3 , leading to a single base substitution, in the twins. This mutation was inherited from the father and paternal grandmother. After 3 mo of treatment with a gonadotropin-releasing hormone analog, levels of LH, follicle-stimulating hormone, and estradiol in the proband’s sister returned to normal levels. CONCLUSION Here, we report a rare mutation (c.841C>T) in MKRN3 in identical twin sisters with CPP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports

Jiang¹,

YanQiong²,

Yuan³

et al. 2021

WJCC

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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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Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination

Magnotto

Mancini

Bird

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. Objective To screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Setting Five academic medical institutions. Participants Eighty-four unrelated children with CPP (79 females, 5 males) and, when available, their first-degree relatives. Design Sanger sequencing of MKRN3 and DLK1 5’ upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Results Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, two were previously identified in patients with CPP, and one is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum LH and FSH compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. Conclusions MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.

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A novel heterozygous MKRN3 nonsense mutation in a Chinese girl with idiopathic central precocious puberty

Cited by 5 publications

References 32 publications

Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports

Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports

Genetic causes of central precocious puberty

Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination

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