RMRP (RNA component of mitochondrial RNA processing endoribonuclease)

2007-12-01   Pia Hermanns , Kerstin Reicherter , Brendan Lee 

Centre for Pediatrics, Adolescent Medicine, pediatric genetics section, Freiburg University Hospital, Germany (PH, KR) ; Howard Hughes Medical Institute (BL) ; Baylor College of Medicine, Department of Molecular, Human Genetics, Houston, TX, USA (BL)

Identity

HGNC
LOCATION
9p13.3
IMAGE
Atlas Image
LEGEND
Figure 1: Cartoon of the RMRP genomic gene structure. The RMRP gene is an intronless gene that is 267 bp long (violet). The promoter region contains a SP1 binding site (blue), an octamer (red), a proximal sequence element (PSE) (green) and a TATA box (yellow).
LOCUSID
ALIAS
CHH,NME1,RMRPR,RRP2
FUSION GENES

DNA/RNA

Note

RMRP is the RNA component of the RNase MRP protein complex. It functions as a RNA and is not translated into a protein.
Atlas Image
Figure 2: Expression pattern of the Rmrp gene. A: in situ hybridization of an E15.5 mouse embryo B: adult human Multiple tissue Northern Blot. Rmrp is ubiquitously expressed in human and mouse. H: hypertrophic chondrocytes.

Transcription

The RMRP gene is transcribed by the DNA dependent RNA polymerase III. The gene contains typical sequence elements of a RNA Pol III type 3 promoter. The core sequence elements such as the PSE element and a TATA box can be found upstream of the transcription initiation site of the RMRP gene. In addition, transcription factor binding sites like a SP1 binding element and an octamer (recruits the transcription factor Oct-1) sequence could serve as distal sequence elements (DSE) to enhance the transcription of RMRP similar to the DSE element of the human U6 snRNA gene.
Expression RMRP is strongly and ubiquitously expressed in mouse embryos (as an example an E15.5 mouse embryo is shown). In bone Rmrp is more strongly expressed in hypertrophic chondrocytes and pericondrium than in the zone of proliferating chondrocytes. There is also very strong expression in the epiphysis. In humans RMRP shows also a very strong expression in adult tissues. A little weaker expression is observed in skeletal muscle when compared to the GAPDH hybridization control. In Xenopus laevis oocytes RMRP is stronger expressed in developmental stages with a higher content of mitochondria.
Function RMRP has been mostly studied in yeast and multiple functions have been attributed to this ribonucleoprotein complex, called RNase MRP. The yeast orthologues gene is called nme1. Firstly, it plays a role in mitochondrial DNA replication. It cleaves the RNA primer of RNA/DNA hybrid. This hybrid formation initiates the mitochondrial DNA replication. It is also involved in the RNA primer formation. Secondly, RMRP is involved in the progression of the cell cycle at the end of mitosis. Some nme1 mutants arrest in the late cycle of mitosis. These mutants present morphologically as large budded cells with dumbbell-shaped nuclei, and also exhibit extended spindles. This cell cycle arrest might be due to an increased level of CLB2. In wild type yeast strains the 5UTR of CLB2 is cleaved by the RNase MRP complex. This causes a rapid degradation of the CLB2 mRNA, which leads to a cell cycle progression. Thirdly, RMRP also plays a role in the ribosomal RNA processing. In yeast, it cleaves pre-ribosomal RNA at the A3 site thus helps the maturation of the short and active form of the 5.8S rRNA.
Homology RNase P is also a ribonucleoprotein endoribonuclease that is mainly involved in tRNA precursor maturation. RNase P and RNase MRP have eight proteins in common. The protein RPR2p is unique to the RNase P complex. In yeast two RNase MRP specific proteins have been identified; snm1 and rmp1. The loss of function of snm1 leads to a defect in the chromosome segregation during mitosis. But the exact mechanism is not understood yet.

Proteins

Atlas Image
Figure 3: Cartoon of the ribosomal RNA processing. If Rnase MRP cleaves the 27SA2 rRNA at the A3 site, this leads to the formation of the short form of the 5.8S rRNA (5.8SS). In a second, less effective alternative pathway, the 27SA2 rRNA is directly cleaved at the B1L site that leads at the end to the formation of the long form of the 5.8S rRNA (5.8SL).

Mutations

Note

So far 93 different mutations have been identified in CHH patients. These include 24 promoter mutations that are either duplications, triplications or insertions that occur exclusively between the TATA box and the transcription start site. The size of the promoter mutations varies between 6 and 24 bp. In vitro studies have shown that these promoter mutations decrease the level of the RMRP transcript but do not abolish the RNA transcription completely. 69 different mutations in the 267 bp long transcript have been found up to now. 57 of these are single base pair substitutions spread out over the entire transcript. Also 11 small insertions, duplications and deletions have been found. The largest deletion identified so far involves the last 10 bp of the RMRP transcript.
The mutations lead to a significant decrease of the RMRP RNA level in CHH, despite the nature of the mutation. These mutations might influence the secondary structure of the RNA, the binding of the proteins to the RNA or the RNA stability itself.
The most frequently found mutation among CHH patients is a 70 A>G transition mutation with an ancient founder origin established in Finland and is the only mutation found in Amish CHH patients. Patients either carry two mutations in the RMRP transcript or are compound heterozygous for a promoter mutation and a transcript mutation. Interestingly, none of the patients exhibit two promoter mutations.
In addition 11 polymorphisms and 17 rare sequence variants have been observed. This is very remarkable considering the small size of the RMRP gene.
So far no complete deletion of the entire RMRP gene has been observed. This suggests that complete loss of RMRP function might be incompatible with life. This is also supported by the fact that the knock out of the yeast NME1 gene is lethal.

Implicated in

Entity name
Cartilage Hair Hypoplasia (CHH)
Prognosis
The adult height ranges between 111 and 151 cm in males and between 104 and 137 cm in females. Around 20% of Cartilage Hair Hypoplasia patients exhibit recurrent to severe infections. These patients show evidence of immune deficiency in vivo and in vitro.
Atlas Image
Atlas Image
Oncogenesis
A predisposition to certain cancers primarily lymphomas has been reported.

Bibliography

Pubmed IDLast YearTitleAuthors
162447062005Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.Bonafé L et al
121360082002The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis.Cai T et al
35823651987A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication.Chang DD et al
82905781994The RNA of RNase MRP is required for normal processing of ribosomal RNA.Chu S et al
147299432004RNase MRP cleaves the CLB2 mRNA to promote cell cycle progression: novel method of mRNA degradation.Gill T et al
168383292006RMRP mutations in cartilage-hair hypoplasia.Hermanns P et al
168325782006Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia.Hirose Y et al
91192231997RNase mitochondrial RNA processing correctly cleaves a novel R loop at the mitochondrial DNA leading-strand origin of replication.Lee DY et al
86025111996Accurate processing of a eukaryotic precursor ribosomal RNA by ribonuclease MRP in vitro.Lygerou Z et al
171899382007RNase MRP RNA and human genetic diseases.Martin AN et al
170151502006A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia.Muñoz-Robles J et al
146086462003RMRP mutations in Japanese patients with cartilage-hair hypoplasia.Nakashima E et al
128889882003The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases.Ridanpää M et al
79589201994Characterization of a unique protein component of yeast RNase MRP: an RNA-binding protein with a zinc-cluster domain.Schmitt ME et al
123816592002Recruitment of RNA polymerase III to its target promoters.Schramm L et al
107134582000Mutational analysis of the RNA component of Saccharomyces cerevisiae RNase MRP reveals distinct nuclear phenotypes.Shadel GS et al
162522392005Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator.Thiel CT et al
177018972007Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum.Thiel CT et al
16903921990Characterization of human MRP/Th RNA and its nuclear gene: full length MRP/Th RNA is an active endoribonuclease when assembled as an RNP.Topper JN et al
150965762004Mutual interactions between subunits of the human RNase MRP ribonucleoprotein complex.Welting TJ et al

Other Information

Locus ID:

NCBI: 6023
MIM: 157660
HGNC: 10031
Ensembl: ENSG00000269900

Variants:

dbSNP: 6023
ClinVar: 6023
TCGA: ENSG00000269900
COSMIC: RMRP

RNA/Proteins

Pathways

PathwaySourceExternal ID
Ribosome biogenesis in eukaryotesKEGGko03008
Ribosome biogenesis in eukaryotesKEGGhsa03008

References

Pubmed IDYearTitleCitations
197011822009An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA.151
271921212016LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer.50
162522392005Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator.38
240093122014Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia.34
162540022005Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia.32
177018972007Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum.23
281154652017Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing.21
279069632016LncRNA-RMRP Acts as an Oncogene in Lung Cancer.20
119400902002RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.16
121078192002Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.16

Citation

Pia Hermanns ; Kerstin Reicherter ; Brendan Lee

RMRP (RNA component of mitochondrial RNA processing endoribonuclease)

Atlas Genet Cytogenet Oncol Haematol. 2007-12-01

Online version: http://atlasgeneticsoncology.org/gene/44001/rmrp