pleiotropic human disease. Responsible for this disease is a mutation in the RNase MRP RNA gene (RMRP), a non-coding RNA gene. RMRP was the first non-coding nuclear RNA gene found to cause disease.[3]
Mechanism and mutation effects
RNase MRP and its role in
rRNA
.
Recent data that has been gathered using several temperature-sensitive RNase MRP
mutants that showed that inactivation of RNase MRP leading to severe reduction of the abundance of all early intermediates
in the typical rRNA processing pathway. However, the transcription of the rRNA precursor is not affected, thus suggesting that RNase MRP plays a key role in the processing of rRNA beyond the cleavage of the A3 site in ITS1.
Further research in Yeast cell RNase MRP has shown a potential role in the regulation of the cell cycle. RNase MRP mutations led to missegregation of
tRNA. RNase MRP is found only in eukaryotes, and is involved in rRNA processing, which is the conversion of preribosomal RNA into mature rRNA through splicing, modifications, and cleavage. The exact mechanism is described above.[5]
Evolutionary link
These two
phylogenetic relation between these two important ribonucleoprotein complexes.[5]
(OS) are diseases associated with mutated and (or) dysfunctional RNAse MRP activity, hence, the RMRP gene.
Disease
Abbreviation
Location of mutation
Mutation in RNAse MRP protein or RNA in RNAse MRP?
Symptoms
Cartilage–hair hypoplasia
CHH
1.Insertion, duplication or triplication at promoter or 2. In RNA transcribed by RNAse MRP
RNA in RNAse MRP
Patients have short stature, skeletal anomalies, blood and immune problems, and fine, light-colored hair
Metaphyseal dysplasia without hypotrichosis
MDWH
1. on RMRP Gene-->common insertion being -21-20insTCTGTGAAGCTGGGGAC on paternal allele or 2. 218A-->G point mutation occurring on maternal allele
RNA in RNAse MRP
Patients unable to produce new tubular structures in metaphyses of long bones. This results in porous and expanded long bones
Anauxetic dysplasia
AD
Homozygous insertion mutation and two compound heterozygous mutations
RNA in RNAse MRP
Early onset of extremely short stature. Adults typically not exceeding 85 cm in height. Abnormal amount of teeth (less than standard amount). Slight mental retardation.
Kyphomelic dysplasia
KD
Mutation (insertion) of T at 194-195 paternal allele and a 63 C-->T point mutation of the maternal allele.
Undetermined
Form of short-limbed dwarfism. Bowing long bones, dysmorphia, flattened vertebrae, and short ribs.
Omenn Syndrome
OS
Three mutations in RMRP gene (specifics unknown at this time)
RNA in RNAse MRP
Patients are immunodeficient and have scaly erythroderma and severe reddening of skin.
Cartilage–hair hypoplasia
triplication occurs at the promoter of the RNAse MRP gene between the TATA box
and the transcription initiation site. This causes the initiation of RNAse MRP to be slow, or to not occur at all.
The second category consists of mutations that are in the transcribed RNA made by the RNAse MRP. Patients with CHH have been identified to have over 70 different mutations in the RNA transcript made by RNAse MRP, whereas around 30 distinct mutations have been identified in the promoter region of the RNAse MRP gene. Most CHH patients have a combination of either a promoter mutation in one allele along with a RNAse MRP RNA mutation in the other allele, or a combination of two RNAse MRP RNA mutations in both alleles. The fact that there is not often a mutation in the promoter region in both alleles shows the lethality of not having this RNA present that is transcribed by RNAse MRP.[6][7][8]
Metaphyseal dysplasia without hypotrichosis
Metaphyseal
metaphyses of long bones. People diagnosed with MDWH will therefore tend to experience porous and expanded long bones. The mutation occurs on the RMRP gene in MDWH; the common insertion being (-21-20 insTCTGTGAAGCTGGGGAC) on the paternal allele and a 218A→G point mutation occurring on the maternal allele. MDWH is most likely a variant of CHH. They are the same in that they both display short stature. Some of the same genes involved in the mutations in CHH are the same genes that are mutated in MDWH.[9] These two diseases do differ in that MDWH lacks immunodeficiency and other skeletal features found in CHH patients.[3]
Anauxetic dysplasia
AD is an
autosomal recessive spondylometaepiphyseal dysplasia typically characterized by an early (prenatal) onset of extremely short stature and adults that do not typically exceed 85 cm in height. A less than normal amount of teeth and slight mental retardation are also typical of AD. The associated mutation(s) are a homozygous insertion mutation and two compound heterozygous mutations.[3] Mutations in the promoter 5' regulatory region have been associated with this severe skeletal disease. Other names used to describe this condition are spondylometaepiphyseal dysplasia, anauxetic type, spondylometaepiphyseal dysplasia, Menger type.[10]
Kyphomelic dysplasia
KD is a form of short-limbed dwarfism. Characteristics of KD are bowing of long bones, dysmorphia, flattened vertebrae, and short ribs. Femoral bowing is the hallmark diagnostic characteristic of KD. Novel mutations have been discovered in the RMRP gene of a single patient with KD, specifically, a mutation (insertion) of T at 194-195 paternal allele and a 63C-->T point mutation of the maternal allele. As with OS, the MSRP gene has not been strictly linked to the diseases but current research is suggestive that the MSRP gene is a factor. KD has been observed in very few patients yet this sublethal disease remains relevant to discussions of the distinct manifestations of minimal change disease. KD is rather similar to several forms of MCD in that it exhibits combined immune deficiency and aplastic anemia.[3]
Omenn syndrome
Omenn syndrome (OS) is a severe
immunodeficient meaning their immune system is compromised and cannot properly fight infections resulting in serious secondary illnesses.[3]