DFN2 or Postlingual nonsyndromic hearing impairment, however rare, but is a severe genetic defect found among males. It is progressive by nature and is mainly caused by mutations linked to the gene PRPS1, located in the NFD2 locus. This very disease is a form of progressive deafness that has been reported to have numerous amount of cases from United States, United Kingdom and China, with male kids developing this disease from the age of 5-15.
PRSP1 gene encodes an enzyme that catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate. This kind of reaction yielding into the phosphoribosylation is typically essential for major purposes including, purine metabolism and nucleotide biosynthesis.
The gene has been found to be located on X chromosome according to the Entrez entry and the mutations occuring in this gene can cause a number of genetic and chemical defects including phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive type 5 and Arts Syndrome.It has a major role in nucleotide synthesis, where it catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that has been known to be necessary for the nucleotide synthesis. PRSP1 gene is also known to play an important role in magnesium ion binding, ribose phosphate diphosphokinase activity, ATP binding, kinase activity and protein homodimerization activity.
Xuezhong Liu, Dongyi Han et al. conducted a research on a large Chinese family that was reported to have X-linked postlingual nonsyndromic hearing impairment (DFN2). What actually happens in DFN2 (in contrast from the non-sufferers who have no mutations whatsoever linked to the PRSP1 gene) is that the critical linkage experience mutations resulting in a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that happens to overlap the DFN2 locus. When the gene PRSP1 was screened for mutations, four mis-sense mutation were found to have occured in the gene. The research also included three other families with the same disease. These four found mutations led to a loss of activity in PRPP synthetase 1 resulting into progressive hearing loss in males.
These four mutations can be categorized into two classes; the first class consists of those that mostly affect the local structure, specifically, p.A87T and p.I290T; the second class consists of those that affect the trimer interface, specifically, p.D65N and p.G306R. Asp65 interacts in the hexamer surface with Glu62 and Asn64. The Ala87 located in the beta sheet of the hydrophobic region of N terminal domain, changes to a more intense bulky and more polar threonine side chain, leading to destabilization of the surrounding (tightly-packed) hydrophobic area. Another important factor that plays an important role here is Ile290 which is located at the edge of the central β sheet on the surface of the PRS-I protein of the C-terminal domain. Now, if the threonine side chain changes to a smaller but more polar stage, it will lead to a destabilization of this region.
The p.G306R change has been found to be present at the surface of the protein, near the center of the hexamer. Subsequent modification experiments point out that the introduction of the much larger arginine side chain in PRSP1, will be taken in freely due to the nature of the arginine side, pointing outwards. In contrast to this, however, stability of PRSP1 could get changed to a noticeable level that would be resulting due to the new accommodations near the center of the hexamer in the form of introduction of three charged arginine side chains.
Liu, Han et al. proved their results in silico by structural analysis and also in vitro by utilizing the enzymatic activity assays in erythrocytes and fibroblasts that were obtained from the patients. When in situ hybridization was conducted, the expression of PRSP1 in murine vestibular and cochlea hair cells was demonstrated, with a continuous and progressive expression in hair cells and also in the postnatal expression of spiral ganglion.
When the structural protein changes were compared in the aforementioned mutations, the mutations resulting in the mildest symptoms were found to have the minimum effect on the PRS-I structure. (For your knowledge, the PRS-1 gene is among the family of three genes that comes from the phosphoribosylpyrophosphate synthetases (PRSs) that are known to catalyze the first step of the nucleotide synthesis.) The mutations occurring in DFN2 can either affect the trimer surface or the stability of PRS-I. The ones causing disturbance in the stability of PRS-I causes PRS-I to get super-activated which leads to a substantial effect on the allosteric sites I and II. Moreover, the mutations that appear in CMTX5 (that affects the stability of trimer interface and hence the consequential interaction taking place there) and the Arts syndrome (that largely disrupt the overall PRS-I structure), tend to affect the ATP-binding site too, apart from the allosteric sites.
This groundbreaking discovery of the second identified gene associated with X-linked nonsyndromic deafness and its role in the development of middle ear, the gene PRSP1 is believed to offer new approaches to gain a better insight into the genetic defects and their treatment. Considering the results and evidences obtained from the research, now scientists can doctors can specifically develop a targeted therapeutic treatment for the patients suffering from DFN2. Not only this discovery allow us to understand the core reasons of the progressive hearing loss in males but also provides us with the novel therapeutic opportunities.
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