MKRN3

Official Full Name

makorin ring finger protein 3

Organism

Homo sapiens

GeneID

7681

Background

The protein encoded by this gene contains a RING (C3HC4) zinc finger motif and several C3H zinc finger motifs. This gene is intronless and imprinted, with expression only from the paternal allele. Disruption of the imprinting at this locus may contribute to Prader-Willi syndrome. An antisense RNA of unknown function has been found overlapping this gene. [provided by RefSeq, Jul 2008]

Synonyms

CPPB2; D15S9; RNF63; ZFP127; ZNF127;

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Detailed Information

The MKRN3 gene (makorin RING-finger protein 3) is at a critical position in the Prader-Willi syndrome (on chromosome 15q11.2). Prader-Willi syndrome is a genetic disorder characterized by decreased muscle tone in infancy and an increase in appetite, hypogonadism, growth hormone deficiency, mental retardation, and severe emotional behavioral disorders with age. Although MKRN3 is at a critical position in Prader-Willi syndrome, the relationship between MKRN3 and Prader-Willi syndrome is unclear. So far, humans have found 21 mutations in the MKRN3 gene: including 8 frameshift mutations, 10 missense mutations, and 3 nonsense mutations.

Mkrn3 Figure 1. Schematic representation of MKRN3 mechanism of action.（Abreu, A. P., et al.2015）

Relationship Between Central Precocious Puberty and MKRN3

Abreu et al. sequenced the entire exon in 32 patients with central precocious puberty and 8 healthy individuals with a history of precocious puberty. Four new MKRN3 heterozygous mutations were found. Patients with MKRN3 mutations and central precocious puberty inherited mutations from their fathers, and those who inherited MKRN3 mutations from their mothers did not exhibit precocious puberty. This suggests that MKRN3 may be a maternal imprinting gene, which is expressed only by paternal inheritance. Additional studies support this view and suggest that MKRN3 may inhibit targets downstream of the HPG axis rather than activating GnRH neurons. In one study, the researchers performed MKRN3 gene sequencing on 215 patients with central precocious puberty and found five new heterozygous mutations in eight patients, all of which were genetically inherited from the father. The idea that MKRN3 is a maternal imprinted gene is also demonstrated.

Association of MKRN3 with Familial Central Precocious Puberty

In one case analysis, a new MKRN3 heterozygous missense mutation (p.c340g) was found in a girl with central precocious puberty and a younger brother with early development. The mutation was also tested in their father and grandmother. The investigators hypothesized that if a family has a history of central precocious puberty or early adolescence, it can be considered as a mutation in MKRN3. Abreu et al. also suggested that the loss of function of MKRN3 mutations may lead to familial central precocious puberty. A total of 46 patients with central precocious puberty were enrolled in the study (28 patients had a history of familial precocious puberty and 18 patients had a family history of asexual precocity). MKRN3 gene mutations were detected in 13 patients with a history of familial precocious puberty.

The researchers sequenced the MKRN3 gene in 60 girls with idiopathic central precocious puberty (23 girls with a family history of precocious puberty), and obtained three MKRN3 gene mutations, p.Arg328Cys, p.Cys410Ter, p.Pro160Cysfs*14, wherein p.Cys410Ter is a novel mutation. These mutations are inherited from the patient's father. The investigator followed a 4-year-old girl with a history of familial precocious puberty. The girl's sister was diagnosed with central precocious puberty at the age of 6 and carried the p. Pro161Argfs*16 mutation inherited from her father. The girl who was followed was experiencing an accelerated rate of growth (9 cm/year) at age 6 and between 6.3 and 6.7 years of age, breast development progressed rapidly (Tanner1-Tanner3) with an elevated LH baseline ( 0.4 IU/L), the girl was quickly diagnosed with precocious puberty and treated.

References:

Settas, N. , Dacouvoutetakis, C. , Karantza, M. , Kanakagantenbein, C. , Chrousos, G. P. , & Voutetakis, A. . (2014). Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the mkrn3 gene. Journal of Clinical Endocrinology & Metabolism, 99(4), 647-51.
Abreu, A. P. , Macedo, D. B. , Brito, V. N. , Kaiser, U. B. , & Latronico, A. C. . (2015). A new pathway in the control of the initiation of puberty: the mkrn3 gene. Journal of Molecular Endocrinology, 54(3), R131-R139.
Hagen C P, et al. Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls[J]. The Journal of Clinical Endocrinology & Metabolism, 2015, 100(5): 1920-1926.

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