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RMRP (RNA component of mitochondrial RNA processing endoribonuclease)

Identity

Other namesCHH
RMRPR
HGNC (Hugo) RMRP
LocusID (NCBI) 6023
Location 9p13.3
Location_base_pair Starts at 35657748 and ends at 35658015 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  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).

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.
 
  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 5'UTR 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.

Protein

 
  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 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.
 
 
Oncogenesis A predisposition to certain cancers primarily lymphomas has been reported.
  

External links

Nomenclature
HGNC (Hugo)RMRP   10031
Cards
AtlasRMRPID44001ch9p21
Entrez_Gene (NCBI)RMRP  6023  RNA component of mitochondrial RNA processing endoribonuclease
GeneCards (Weizmann)RMRP
Ensembl (Hinxton)ENSG00000269900 [Gene_View]  chr9:35657748-35658015 [Contig_View]  RMRP [Vega]
ICGC DataPortalENSG00000269900
cBioPortalRMRP
AceView (NCBI)RMRP
Genatlas (Paris)RMRP
WikiGenes6023
SOURCE (Princeton)
Genomic and cartography
GoldenPath (UCSC)RMRP  -  9p13.3   chr9:35657748-35658015 -  9p21-p12   [Description]    (hg19-Feb_2009)
EnsemblRMRP - 9p21-p12 [CytoView]
Mapping of homologs : NCBIRMRP [Mapview]
OMIM157660   250250   250460   607095   
Gene and transcription
Genbank (Entrez)AA593275 DW422801 DW423815
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NG_017041 NG_033120 NT_008413 NW_001839149 NW_004929342
Consensus coding sequences : CCDS (NCBI)RMRP
Cluster EST : UnigeneHs.587502 [ NCBI ]
CGAP (NCI)Hs.587502
Alternative Splicing : Fast-db (Paris)GSHG0044802
Alternative Splicing GalleryENSG00000269900
Gene ExpressionRMRP [ NCBI-GEO ]     RMRP [ SEEK ]   RMRP [ MEM ]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
DMDM Disease mutations6023
Human Protein AtlasENSG00000269900 [gene] [tissue] [antibody] [cell] [cancer]
Protein Interaction databases
FunCoupENSG00000269900
BioGRIDRMRP
IntegromeDBRMRP
STRING (EMBL)RMRP
Ontologies - Pathways
Ontology : AmiGO
Ontology : EGO-EBI
Protein Interaction DatabaseRMRP
Wikipedia pathwaysRMRP
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)RMRP
snp3D : Map Gene to Disease6023
SNP (GeneSNP Utah)RMRP
SNP : HGBaseRMRP
Genetic variants : HAPMAPRMRP
Exome VariantRMRP
1000_GenomesRMRP 
ICGC programENSG00000269900 
Mutations and Diseases : HGMDRMRP
Mutations and Diseases : intOGenRMRP
Genomic VariantsRMRP  RMRP [DGVbeta]
dbVarRMRP
ClinVarRMRP
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM157660    250250    250460    607095   
MedgenRMRP
GENETestsRMRP
Disease Genetic AssociationRMRP
Huge Navigator RMRP [HugePedia]  RMRP [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneRMRP
Homology/Alignments : Family Browser (UCSC)RMRP
Phylogenetic Trees/Animal Genes : TreeFamRMRP
Chemical/Protein Interactions : CTD6023
Chemical/Pharm GKB GenePA34404
Clinical trialRMRP
Cancer Resource (Charite)ENSG00000269900
Other databases
Probes
Litterature
PubMed27 Pubmed reference(s) in Entrez
CoreMineRMRP
iHOPRMRP
OncoSearchRMRP

Bibliography

A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication.
Chang DD, Clayton DA
The EMBO journal. 1987 ; 6 (2) : 409-417.
PMID 3582365
 
Characterization 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, Clayton DA
Nucleic acids research. 1990 ; 18 (4) : 793-799.
PMID 1690392
 
Yeast site-specific ribonucleoprotein endoribonuclease MRP contains an RNA component homologous to mammalian RNase MRP RNA and essential for cell viability.
Schmitt ME, Clayton DA
Genes & development. 1992 ; 6 (10) : 1975-1985.
PMID 1398074
 
The RNA of RNase MRP is required for normal processing of ribosomal RNA.
Chu S, Archer RH, Zengel JM, Lindahl L
Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (2) : 659-663.
PMID 8290578
 
Characterization of a unique protein component of yeast RNase MRP: an RNA-binding protein with a zinc-cluster domain.
Schmitt ME, Clayton DA
Genes & development. 1994 ; 8 (21) : 2617-2628.
PMID 7958920
 
Accurate processing of a eukaryotic precursor ribosomal RNA by ribonuclease MRP in vitro.
Lygerou Z, Allmang C, Tollervey D, Sˆ©raphin B
Science (New York, N.Y.). 1996 ; 272 (5259) : 268-270.
PMID 8602511
 
RNase mitochondrial RNA processing correctly cleaves a novel R loop at the mitochondrial DNA leading-strand origin of replication.
Lee DY, Clayton DA
Genes & development. 1997 ; 11 (5) : 582-592.
PMID 9119223
 
Mutational analysis of the RNA component of Saccharomyces cerevisiae RNase MRP reveals distinct nuclear phenotypes.
Shadel GS, Buckenmeyer GA, Clayton DA, Schmitt ME
Gene. 2000 ; 245 (1) : 175-184.
PMID 10713458
 
Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia.
Ridanpˆ§ˆ§ M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Mˆ§kitie O, Kaitila I, de la Chapelle A
Cell. 2001 ; 104 (2) : 195-203.
PMID 11207361
 
RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.
Bonafˆ© L, Schmitt K, Eich G, Giedion A, Superti-Furga A
Clinical genetics. 2002 ; 61 (2) : 146-151.
PMID 11940090
 
The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis.
Cai T, Aulds J, Gill T, Cerio M, Schmitt ME
Genetics. 2002 ; 161 (3) : 1029-1042.
PMID 12136008
 
Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.
Ridanpˆ§ˆ§ M, Sistonen P, Rockas S, Rimoin DL, Mˆ§kitie O, Kaitila I
European journal of human genetics : EJHG. 2002 ; 10 (7) : 439-447.
PMID 12107819
 
Recruitment of RNA polymerase III to its target promoters.
Schramm L, Hernandez N
Genes & development. 2002 ; 16 (20) : 2593-2620.
PMID 12381659
 
RMRP mutations in Japanese patients with cartilage-hair hypoplasia.
Nakashima E, Mabuchi A, Kashimada K, Onishi T, Zhang J, Ohashi H, Nishimura G, Ikegawa S
American journal of medical genetics. Part A. 2003 ; 123 (3) : 253-256.
PMID 14608646
 
The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases.
Ridanpˆ§ˆ§ M, Jain P, McKusick VA, Francomano CA, Kaitila I
American journal of medical genetics. Part C, Seminars in medical genetics. 2003 ; 121 (1) : 81-83.
PMID 12888988
 
RNase MRP cleaves the CLB2 mRNA to promote cell cycle progression: novel method of mRNA degradation.
Gill T, Cai T, Aulds J, Wierzbicki S, Schmitt ME
Molecular and cellular biology. 2004 ; 24 (3) : 945-953.
PMID 14729943
 
Mutual interactions between subunits of the human RNase MRP ribonucleoprotein complex.
Welting TJ, van Venrooij WJ, Pruijn GJ
Nucleic acids research. 2004 ; 32 (7) : 2138-2146.
PMID 15096576
 
Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.
Bonafˆ© L, Dermitzakis ET, Unger S, Greenberg CR, Campos-Xavier BA, Zankl A, Ucla C, Antonarakis SE, Superti-Furga A, Reymond A
PLoS genetics. 2005 ; 1 (4) : page e47.
PMID 16244706
 
Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia.
Hermanns P, Bertuch AA, Bertin TK, Dawson B, Schmitt ME, Shaw C, Zabel B, Lee B
Human molecular genetics. 2005 ; 14 (23) : 3723-3740.
PMID 16254002
 
Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator.
Thiel CT, Horn D, Zabel B, Ekici AB, Salinas K, Gebhart E, Rˆºschendorf F, Sticht H, Spranger J, Mˆºller D, Zweier C, Schmitt ME, Reis A, Rauch A
American journal of human genetics. 2005 ; 77 (5) : 795-806.
PMID 16252239
 
RMRP mutations in cartilage-hair hypoplasia.
Hermanns P, Tran A, Munivez E, Carter S, Zabel B, Lee B, Leroy JG
American journal of medical genetics. Part A. 2006 ; 140 (19) : 2121-2130.
PMID 16838329
 
Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia.
Hirose Y, Nakashima E, Ohashi H, Mochizuki H, Bando Y, Ogata T, Adachi M, Toba E, Nishimura G, Ikegawa S
Journal of human genetics. 2006 ; 51 (8) : 706-710.
PMID 16832578
 
A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia.
Muˆ±oz-Robles J, Allende LM, Clemente J, Calleja S, Varela P, Gonzalez L, de Pablos P, Paz E, Morales P
Immunobiology. 2006 ; 211 (9) : 753-757.
PMID 17015150
 
RNase MRP RNA and human genetic diseases.
Martin AN, Li Y
Cell research. 2007 ; 17 (3) : 219-226.
PMID 17189938
 
Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum.
Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A
American journal of human genetics. 2007 ; 81 (3) : 519-529.
PMID 17701897
 
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Contributor(s)

Written12-2007Pia Hermanns, Kerstin Reicherter, Brendan Lee
Centre for Pediatrics and Adolescent Medicine, pediatric genetics section, Freiburg University Hospital, Germany (PH, KR) ; Howard Hughes Medical Institute (BL) ; Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA (BL)

Citation

This paper should be referenced as such :
Hermanns, P ; Reicherter, K ; Lee, B
RMRP (RNA component of mitochondrial RNA processing endoribonuclease)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):328-333.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/RMRPID44001ch9p21.html

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