Papillorenal syndrome pathophysiology: Difference between revisions
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{{CMG}} | {{CMG}} {{AE}} {{Shivam Singla}} | ||
==Overview== | ==Overview== | ||
The known cause of the [[Papillorenal syndrome]] is mutation of a copy of the [[Pax genes|PAX2 gene]], a gene which is important in the development of both the eye and the kidney. However, approximately half of patients with [[Papillorenal syndrome]] do not have defects in the ''Pax2''. This suggests that other genes play a role in the development of the syndrome, though few downstream effectors of ''Pax2'' have been identified. | The known cause of the [[Papillorenal syndrome]] is [[mutation]] of a copy of the [[Pax genes|PAX2 gene]], a [[gene]] which is important in the development of both the [[eye]] and the [[kidney]]. However, approximately half of patients with [[Papillorenal syndrome]] do not have defects in the ''[[Pax2]]''. This suggests that other [[genes]] play a role in the development of the [[syndrome]], though few downstream effectors of ''[[Pax2]]'' have been identified. | ||
==Pathophysiology== | ==Pathophysiology== | ||
[[File:Papillorenal Syndrome 11.jpg|thumb| | [[File:Papillorenal Syndrome 11.jpg|thumb|358x358px|'''Papillorenal Syndrome Genetics Related to PAX2 Gene.''', | ||
https://disorders.eyes.arizona.edu/disorders/papillorenal-syndrome]] | |||
===''Pax2'' mutations=== | ===''Pax2'' mutations<ref name="pmid10466411">{{cite journal |vauthors=Eccles MR, Schimmenti LA |title=Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations |journal=Clin. Genet. |volume=56 |issue=1 |pages=1–9 |date=July 1999 |pmid=10466411 |doi=10.1034/j.1399-0004.1999.560101.x |url=}}</ref>=== | ||
The majority of mutations occur in exons 2,3 and 4, which encode the paired domain and frame shift mutations that lead to a null allele.<ref name="schim">http://www.d.umn.edu/biology/documents/Schimmenti.pdf)</ref> The missense mutations appear to disrupt [[hydrogen bond|hydrogen bonds]], leading to decreased transactivation of ''Pax2'', but do not seem to effect nuclear localization, steady state mRNA levels, or the ability of ''Pax2'' to bind to its DNA consensus sequence.<ref name="genetics">{{cite journal |author=Alur RP, Vijayasarathy C, Brown JD, ''et al.'' |title=Papillorenal syndrome-causing missense mutations in PAX2/Pax2 result in hypomorphic alleles in mouse and human |journal=PLoS Genet. |volume=6 |issue=3 |pages=e1000870 |year=2010 |month=March |pmid=20221250 |pmc=2832668 |doi=10.1371/journal.pgen.1000870 |url=}}</ref> Mutations related to the disease have also been noted in exons 7,8, and 9, with milder phenotypes than the other mutations.<ref name="schim">{{cite pmid|20301624}}</ref> | The majority of [[mutations]] occur in exons 2,3 and 4, which encode the paired domain and [[frame shift mutations]] that lead to a null [[allele]].<ref name="schim">http://www.d.umn.edu/biology/documents/Schimmenti.pdf)</ref> The [[missense]] [[mutations]] appear to disrupt [[hydrogen bond|hydrogen bonds]], leading to decreased transactivation of ''[[Pax2]]''<ref name="pmid29333833">{{cite journal |vauthors=Ruiz Del Olmo Izuzquiza I, Romero Salas Y, Rodríguez Valle A, González Viejo I, Justa Roldán ML |title=[Infrequent mutation in renal-coloboma syndrome: case report and review] |language=Spanish; Castilian |journal=Arch Argent Pediatr |volume=116 |issue=1 |pages=e106–e109 |date=February 2018 |pmid=29333833 |doi=10.5546/aap.2018.e106 |url=}}</ref>, but do not seem to effect nuclear localization, steady state [[Messenger RNA|mRNA]] levels, or the ability of ''Pax2'' to bind to its [[DNA]] consensus sequence.<ref name="genetics">{{cite journal |author=Alur RP, Vijayasarathy C, Brown JD, ''et al.'' |title=Papillorenal syndrome-causing missense mutations in PAX2/Pax2 result in hypomorphic alleles in mouse and human |journal=PLoS Genet. |volume=6 |issue=3 |pages=e1000870 |year=2010 |month=March |pmid=20221250 |pmc=2832668 |doi=10.1371/journal.pgen.1000870 |url=}}</ref> Mutations related to the disease have also been noted in exons 7,8, and 9, with milder [[phenotypes]] than the other mutations.<ref name="schim">{{cite pmid|20301624}}</ref> | ||
===Recent studies=== | ===Recent studies=== | ||
''Pax2'' is expressed in the kidney, midbrain, hindbrain, cells in the spinal column, developing ear, and developing eye. [[Zygosity|Homozygous]] negative ''Pax2'' mutation is lethal, but heterozygote mutants showed many symptoms of papillorenal syndrome, including optic nerve dysplasia with abnormal vessels emerging from the periphery of the [[optic cup]] and small dysplastic kidneys. It is shown that ''Pax2'' is under upstream control of [[Shh]] in both [[mice]] and [[zebrafish]], which is expressed in the precordial plate.<ref name="schim">{{cite pmid|20301624}}</ref>[[File: Autosomal Dominant.png|thumb|'''Autosomal Dominant Mode Of Transmission In Papillorenal Syndrome''', | ''Pax2'' is expressed in the [[kidney]], [[midbrain]], [[hindbrain]], cells in the [[spinal column]], developing ear, and developing eye. [[Zygosity|Homozygous]] negative ''Pax2'' mutation is lethal, but [[Heterozygote|heterozygote mutants]] showed many symptoms of [[papillorenal syndrome]], including optic nerve dysplasia with abnormal vessels emerging from the periphery of the [[optic cup]] and small [[Dysplastic change|dysplastic]] [[kidneys]]. It is shown that ''Pax2'' is under upstream control of [[Shh]] in both [[mice]] and [[zebrafish]], which is expressed in the precordial plate.<ref name="schim">{{cite pmid|20301624}}</ref>[[File: Autosomal Dominant.png|thumb|'''Autosomal Dominant Mode Of Transmission In Papillorenal Syndrome''', | ||
https://disorders.eyes.arizona.edu/handouts/papillorenal-syndrome]] | https://disorders.eyes.arizona.edu/handouts/papillorenal-syndrome]] | ||
''PAX2'' gene mutation is expressed in the development of Kidneys, Otic, optic cup and, midbrain-hindbrain boundary. For pathogenesis, The PAX2 mutations have believed to cause the loss of function of one allele known as haploinsufficiency. This PAX2 haploinsufficiency is mostly seen in the conditions associated with the ocular, urogenital, and other abnormalities in humans. Some of the patients with Renal coloboma syndrome also reported having missense mutations. | ''[[PAX2]]'' gene mutation is expressed in the development of [[Kidneys]], Otic, optic cup and, [[midbrain]]-[[hindbrain]] boundary. For pathogenesis, The PAX2 mutations have believed to cause the loss of function of one [[allele]] known as haploinsufficiency. This [[PAX2]] haploinsufficiency is mostly seen in the conditions associated with the [[ocular,]] [[urogenital]], and other abnormalities in humans. Some of the patients with [[Renal-coloboma syndrome|Renal coloboma syndrome]] also reported having missense mutations. | ||
The exact mechanism by which this causes the disease is still not explained. Scientists have explored the association between this mouse [[mutation]] with the paired domain mutation usually seen in [[humans]], The science has tried to explain the expression of mutant proteins in vitro as well as in vivo at a slow pace and lower level as compared to with [[wild type]] protein. | |||
The patients with missense mutations in ''[[PAX2]]''<ref name="urlPAX2-Related Disorder - GeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1451/ |title=PAX2-Related Disorder - GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref> will develop [[Papillorenal syndrome]] due to the hypomorphic nature of the [[alleles]] and the residual function of these couldn't suppress the development of the [[ocular]] and [[renal]] disease. | |||
'''Genetics''' | |||
Renal coloboma syndrome or papillorenal syndrome is an [[autosomal dominant]] disorder that mainly results due to the mutation in the [[PAX2]] gene. This mutation is located on the chromosome 10q24.3-q25.1.[[Papillorenal syndrome]] is an autosomal dominant disorder that results from a mutation of one copy of the [[Pax2]] [[gene]], located on chromosome 10q24.3-q25.1. | |||
The gene is related to the development of [[eyes]] and the [[kidneys]] | |||
Autosomal dominant inheritance- The gene for the [[papillorenal syndrome]] is located on an autosome and the one mutated copy of the [[gene]] is good enough to cause the [[Renal-coloboma syndrome|renal coloboma syndrome]] when inherited from the parent to offspring. | |||
<br /> | <br /> | ||
Latest revision as of 22:16, 28 September 2020
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shivam Singla, M.D.[2]
Overview
The known cause of the Papillorenal syndrome is mutation of a copy of the PAX2 gene, a gene which is important in the development of both the eye and the kidney. However, approximately half of patients with Papillorenal syndrome do not have defects in the Pax2. This suggests that other genes play a role in the development of the syndrome, though few downstream effectors of Pax2 have been identified.
Pathophysiology
Pax2 mutations[1]
The majority of mutations occur in exons 2,3 and 4, which encode the paired domain and frame shift mutations that lead to a null allele.[2] The missense mutations appear to disrupt hydrogen bonds, leading to decreased transactivation of Pax2[3], but do not seem to effect nuclear localization, steady state mRNA levels, or the ability of Pax2 to bind to its DNA consensus sequence.[4] Mutations related to the disease have also been noted in exons 7,8, and 9, with milder phenotypes than the other mutations.[2]
Recent studies
Pax2 is expressed in the kidney, midbrain, hindbrain, cells in the spinal column, developing ear, and developing eye. Homozygous negative Pax2 mutation is lethal, but heterozygote mutants showed many symptoms of papillorenal syndrome, including optic nerve dysplasia with abnormal vessels emerging from the periphery of the optic cup and small dysplastic kidneys. It is shown that Pax2 is under upstream control of Shh in both mice and zebrafish, which is expressed in the precordial plate.[2]
PAX2 gene mutation is expressed in the development of Kidneys, Otic, optic cup and, midbrain-hindbrain boundary. For pathogenesis, The PAX2 mutations have believed to cause the loss of function of one allele known as haploinsufficiency. This PAX2 haploinsufficiency is mostly seen in the conditions associated with the ocular, urogenital, and other abnormalities in humans. Some of the patients with Renal coloboma syndrome also reported having missense mutations.
The exact mechanism by which this causes the disease is still not explained. Scientists have explored the association between this mouse mutation with the paired domain mutation usually seen in humans, The science has tried to explain the expression of mutant proteins in vitro as well as in vivo at a slow pace and lower level as compared to with wild type protein.
The patients with missense mutations in PAX2[5] will develop Papillorenal syndrome due to the hypomorphic nature of the alleles and the residual function of these couldn't suppress the development of the ocular and renal disease.
Genetics
Renal coloboma syndrome or papillorenal syndrome is an autosomal dominant disorder that mainly results due to the mutation in the PAX2 gene. This mutation is located on the chromosome 10q24.3-q25.1.Papillorenal syndrome is an autosomal dominant disorder that results from a mutation of one copy of the Pax2 gene, located on chromosome 10q24.3-q25.1.
The gene is related to the development of eyes and the kidneys
Autosomal dominant inheritance- The gene for the papillorenal syndrome is located on an autosome and the one mutated copy of the gene is good enough to cause the renal coloboma syndrome when inherited from the parent to offspring.
References
- ↑ Eccles MR, Schimmenti LA (July 1999). "Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations". Clin. Genet. 56 (1): 1–9. doi:10.1034/j.1399-0004.1999.560101.x. PMID 10466411.
- ↑ 2.0 2.1 2.2 http://www.d.umn.edu/biology/documents/Schimmenti.pdf)
- ↑ Ruiz Del Olmo Izuzquiza I, Romero Salas Y, Rodríguez Valle A, González Viejo I, Justa Roldán ML (February 2018). "[Infrequent mutation in renal-coloboma syndrome: case report and review]". Arch Argent Pediatr (in Spanish; Castilian). 116 (1): e106–e109. doi:10.5546/aap.2018.e106. PMID 29333833.
- ↑ Alur RP, Vijayasarathy C, Brown JD; et al. (2010). "Papillorenal syndrome-causing missense mutations in PAX2/Pax2 result in hypomorphic alleles in mouse and human". PLoS Genet. 6 (3): e1000870. doi:10.1371/journal.pgen.1000870. PMC 2832668. PMID 20221250. Unknown parameter
|month=ignored (help) - ↑ "PAX2-Related Disorder - GeneReviews® - NCBI Bookshelf".