Disease relevance of RMRP

• Homozygosity mapping led to the identification of novel mutations in the RMRP gene, which was previously known to cause two milder types of short stature with susceptibility to cancer, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis [1].
• Transcriptional profiling of CHH patient RNAs showed upregulation of several cytokines and cell cycle regulatory genes, one of which has been implicated in chondrocyte hypertrophy [2].
• Recent studies of cartilage-hair hypoplasia (CHH), a form of short-limbed dwarfism, have shown that all affected individuals have a cellular proliferation defect that results in a cellular immunodeficiency [3].
• Gene products mutated in the inherited bone marrow failure syndromes dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) are all predicted to be involved in different aspects of ribosome synthesis [4].
• Hirschsprung disease associated with severe cartilage-hair hypoplasia [5].

Psychiatry related information on RMRP

• For this reason, relevant immune defense mechanisms that may be responsible for maintaining intact host defenses in the majority of CHH individuals were studied [3].

High impact information on RMRP

• We describe numerous mutations in the untranslated RMRP gene that cosegregate with the CHH phenotype [6].
• We conclude that mutations in RMRP cause CHH by disrupting a function of RNase MRP RNA that affects multiple organ systems [6].
• The recessively inherited developmental disorder, cartilage-hair hypoplasia (CHH) is highly pleiotropic with manifestations including short stature, defective cellular immunity, and predisposition to several cancers [6].
• Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis [7].
• Preservation of spontaneous NK activity and loss of all forms of culture-induced cytotoxicity was associated with an increase in the proportion of lymphocytes bearing a thymic independent NK phenotype (OKM1+ OKT3- Fc gamma + low-affinity E+), and a significant decrease in thymic derived OKT3+ cytolytic T cell sub-populations in CHH individuals [3].

Chemical compound and disease context of RMRP

• Lipopolysaccharide-induced hyperglycemia is mediated by CHH release in crustaceans [8].

Biological context of RMRP

• Sequencing 120 alleles from a control group revealed an unusually high density of single-nucleotide polymorphisms in and around the RMRP gene: the biological significance of this finding is unclear [9].
• Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator [1].
• RESULTS: Sequence analysis of the RMRP RNA gene showed that each patient had an insertion-duplication on one allele and a point mutation on the other allele [10].
• The gene (RMRP) for this RNA component of RNAase MRP was assigned to human chromosome 9 and mouse chromosome 4 by Southern blot analyses of 11 human X rodent hybrids and 11 mouse X rodent hybrids with probe pHM1.0 and probe pSP270, respectively [11].
• Evolutionary comparison provides evidence for pathogenicity of RMRP mutations [12].

Anatomical context of RMRP

• RMRP mutations introduced into the yeast ortholog, NME1, exhibited normal mitochondrial function, chromosomal segregation and cell cycle progression, while a CHH fibroblast cell line exhibited normal mitochondrial content [2].
• The short stature and metaphyseal changes associated with cone-shaped epiphyses of the hands should raise the diagnostic possibility of a CHH-related disorder that can then be confirmed by mutation analysis [9].
• Spontaneous natural-killer (NK) activity was present at or above normal levels, but culture-induced specific cytotoxicity and NK-like cytotoxicity as well as NK-like activity by T cell lines were significantly reduced in CHH individuals [3].
• Spontaneous and allogeneic culture-induced (mixed lymphocyte response-MLR) specific and nonspecific (NK-like) cytotoxic mechanisms were analyzed and correlated with lymphocyte subpopulations present in CHH and normal individuals [3].
• Impaired culture generated cytotoxicity with preservation of spontaneous natural killer-cell activity in cartilage-hair hypoplasia [3].

Associations of RMRP with chemical compounds

• CHH lymphocytes could not be stimulated to proliferate normally with B and T cell activators, mitogenic monoclonal antibody (OKT3), allogeneic cells, or chemical activators (Ca++ ionophore A23187 and phorbol myristate acetate) [13].
• In men with AHH, serum AMH levels were also significantly increased when compared to healthy men, but less than in CHH because a persistent testicular T secretion in these patients with less complete gonadotropin deficiency [14].
• A sensitivity-enhanced 1D (1)H spin diffusion experiment, CHH, for determining membrane protein topology is introduced [15].

Other interactions of RMRP

• We show that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation [1].
• Thus, bony defects of varying degrees of severity are seen in short-limb dwarfs, cartilage-hair hypoplasia, and adenosine deaminase (ADA) deficiency [16].
• Analysis of RPS19 in patients with cartilage-hair hypoplasia and severe anemia: preliminary results [17].
• CONCLUSION: Cartilage-hair hypoplasia diagnosis should be considered in patients with metaphyseal chondrodysplasia even in the absence of any extra-skeletal manifestations if no mutation in COL10A1 can be found and the family history is compatible with autosomal recessive inheritance [18].
• To test the validity and sensitivity of the fifteen and sixteen dimensional measures of HRQOL in patients with chondrodysplasias, we examined 121 adults aged 16-54 and 19 adolescents aged 12-15 with achondroplasia, cartilage-hair hypoplasia and diastrophic dysplasia [19].

Analytical, diagnostic and therapeutic context of RMRP

• Spectrum analysis of the mutations and polymorphisms in RMRP showed marked difference between the Japanese and other ethnic groups [20].
• Co-culture experiments failed to reveal any evidence of suppression by CHH mononuclear cells [13].
• An increased apoptosis of both CD4+ and CD8+ T cells, as determined by TUNEL assay, was observed in CHH compared to an age-matched healthy dwarf control [21].
• Our results should encourage the use of BMT in patients with CHH who have profound immunodeficiency.Bone Marrow Transplantation (2006) 38, 751-756. doi:10.1038/sj.bmt.1705520; published online 16 October 2006 [22].
• We describe here the prenatal diagnosis of CHH in a woman who was previously delivered of a similarly affected infant [23].

References